MesenchymAl stromal cells for Traumatic bRain Injury (MATRIx): a study protocol for a multicenter, double-blind, randomised, placebo-controlled phase II trial.

BACKGROUND: Traumatic brain injury (TBI) is a significant cause of death and disability, with no effective neuroprotective drugs currently available for its treatment. Mesenchymal stromal cell (MSC)-based therapy shows promise as MSCs release various soluble factors that can enhance the injury microenvironment through processes, such as immunomodulation, neuroprotection, and brain repair. Preclinical studies across different TBI models and severities have demonstrated that MSCs can improve functional and structural outcomes. Moreover, clinical evidence supports the safety of third-party donor bank-stored MSCs in adult subjects. Building on this preclinical and clinical data, we present the protocol for an academic, investigator-initiated, multicenter, double-blind, randomised, placebo-controlled, adaptive phase II dose-finding study aiming to evaluate the safety and efficacy of intravenous administration of allogeneic bone marrow-derived MSCs to severe TBI patients within 48 h of injury. METHODS/DESIGN: The study will be conducted in two steps. Step 1 will enrol 42 patients, randomised in a 1:1:1 ratio to receive 80 million MSCs, 160 million MSCs or a placebo to establish safety and identify the most promising dose. Step 2 will enrol an additional 36 patients, randomised in a 1:1 ratio to receive the selected dose of MSCs or placebo. The activity of MSCs will be assessed by quantifying the plasmatic levels of neurofilament light (NfL) at 14 days as a biomarker of neuronal damage. It could be a significant breakthrough if the study demonstrates the safety and efficacy of MSC-based therapy for severe TBI patients. The results of this trial could inform the design of a phase III clinical trial aimed at establishing the efficacy of the first neurorestorative therapy for TBI. DISCUSSION: Overall, the MATRIx trial is a critical step towards developing an effective treatment for TBI, which could significantly improve the lives of millions worldwide affected by this debilitating condition. Trial Registration EudraCT: 2022-000680-49.

The Neurological Pupil index for outcome prognostication in people with acute brain injury (ORANGE): a prospective, observational, multicentre cohort study.

BACKGROUND: Improving the prognostication of acute brain injury is a key element of critical care. Standard assessment includes pupillary light reactivity testing with a hand-held light source, but findings are interpreted subjectively; automated pupillometry might be more precise and reproducible. We aimed to assess the association of the Neurological Pupil index (NPi)-a quantitative measure of pupillary reactivity computed by automated pupillometry-with outcomes of patients with severe non-anoxic acute brain injury. METHODS: ORANGE is a multicentre, prospective, observational cohort study at 13 hospitals in eight countries in Europe and North America. Patients admitted to the intensive care unit after traumatic brain injury, aneurysmal subarachnoid haemorrhage, or intracerebral haemorrhage were eligible for the study. Patients underwent automated infrared pupillometry assessment every 4 h during the first 7 days after admission to compute NPi, with values ranging from 0 to 5 (with abnormal NPi being <3). The co-primary outcomes of the study were neurological outcome (assessed with the extended Glasgow Outcome Scale [GOSE]) and mortality at 6 months. We used logistic regression to model the association between NPi and poor neurological outcome (GOSE ≤4) at 6 months and Cox regression to model the relation of NPi with 6-month mortality. This study is registered with ClinicalTrials.gov, NCT04490005. FINDINGS: Between Nov 1, 2020, and May 3, 2022, 514 patients (224 with traumatic brain injury, 139 with aneurysmal subarachnoid haemorrhage, and 151 with intracerebral haemorrhage) were enrolled. The median age of patients was 61 years (IQR 46-71), and the median Glasgow Coma Scale score on admission was 8 (5-11). 40 071 NPi measurements were taken (median 40 per patient [20-50]). The 6-month outcome was assessed in 497 (97%) patients, of whom 160 (32%) patients died, and 241 (47%) patients had at least one recording of abnormal NPi, which was associated with poor neurological outcome (for each 10% increase in the frequency of abnormal NPi, adjusted odds ratio 1·42 [95% CI 1·27-1·64]; p<0·0001) and in-hospital mortality (adjusted hazard ratio 5·58 [95% CI 3·92-7·95]; p<0·0001). INTERPRETATION: NPi has clinically and statistically significant prognostic value for neurological outcome and mortality after acute brain injury. Simple, automatic, repeat automated pupillometry assessment could improve the continuous monitoring of disease progression and the dynamics of outcome prediction at the bedside. FUNDING: NeurOptics.

Changes in upper airways microbiota in ventilator-associated pneumonia.

BACKGROUND: The role of upper airways microbiota and its association with ventilator-associated pneumonia (VAP) development in mechanically ventilated (MV) patients is unclear. Taking advantage of data collected in a prospective study aimed to assess the composition and over-time variation of upper airway microbiota in patients MV for non-pulmonary reasons, we describe upper airway microbiota characteristics among VAP and NO-VAP patients. METHODS: Exploratory analysis of data collected in a prospective observational study on patients intubated for non-pulmonary conditions. Microbiota analysis (trough 16S-rRNA gene profiling) was performed on endotracheal aspirates (at intubation, T0, and after 72 h, T3) of patients with VAP (cases cohort) and a subgroup of NO-VAP patients (control cohort, matched according to total intubation time). RESULTS: Samples from 13 VAP patients and 22 NO-VAP matched controls were analyzed. At intubation (T0), patients with VAP revealed a significantly lower microbial complexity of the microbiota of the upper airways compared to NO-VAP controls (alpha diversity index of 84 ± 37 and 160 ± 102, in VAP and NO_VAP group, respectively, p-value < 0.012). Furthermore, an overall decrease in microbial diversity was observed in both groups at T3 as compared to T0. At T3, a loss of some genera (Prevotella 7, Fusobacterium, Neisseria, Escherichia-Shigella and Haemophilus) was found in VAP patients. In contrast, eight genera belonging to the Bacteroidetes, Firmicutes and Fusobacteria phyla was predominant in this group. However, it is unclear whether VAP caused dysbiosis or dysbiosis caused VAP. CONCLUSIONS: In a small sample size of intubated patients, microbial diversity at intubation was less in patients with VAP compared to patients without VAP.

Multicentre observational study on practice of ventilation in brain injured patients: the VENTIBRAIN study protocol.

INTRODUCTION: Mechanical ventilatory is a crucial element of acute brain injured patients' management. The ventilatory goals to ensure lung protection during acute respiratory failure may not be adequate in case of concomitant brain injury. Therefore, there are limited data from which physicians can draw conclusions regarding optimal ventilator management in this setting. METHODS AND ANALYSIS: This is an international multicentre prospective observational cohort study. The aim of the 'multicentre observational study on practice of ventilation in brain injured patients'-the VENTIBRAIN study-is to describe the current practice of ventilator settings and mechanical ventilation in acute brain injured patients. Secondary objectives include the description of ventilator settings among different countries, and their association with outcomes. Inclusion criteria will be adult patients admitted to the intensive care unit (ICU) with a diagnosis of traumatic brain injury or cerebrovascular diseases (intracranial haemorrhage, subarachnoid haemorrhage, ischaemic stroke), requiring intubation and mechanical ventilation and admission to the ICU. Exclusion criteria will be the following: patients aged <18 years; pregnant patients; patients not intubated or not mechanically ventilated or receiving only non-invasive ventilation. Data related to clinical examination, neuromonitoring if available, ventilator settings and arterial blood gases will be recorded at admission and daily for the first 7 days and then at day 10 and 14. The Glasgow Outcome Scale Extended on mortality and neurological outcome will be collected at discharge from ICU, hospital and at 6 months follow-up. ETHICS AND DISSEMINATION: The study has been approved by the Ethic committee of Brianza at the Azienda Socio Sanitaria Territoriale-Monza. Data will be disseminated to the scientific community by abstracts submitted to the European Society of Intensive Care Medicine annual conference and by original articles submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04459884.

Acute Distress Respiratory Syndrome After Subarachnoid Hemorrhage: Incidence and Impact on the Outcome in a Large Multicenter, Retrospective Cohort.

BACKGROUND: Respiratory complications are frequently reported after aneurismal subarachnoid hemorrhage (aSAH), even if their association with outcome remains controversial. Acute respiratory distress syndrome (ARDS) is one of the most severe pulmonary complications after aSAH, with a reported incidence ranging from 11 to 50%. This study aims to assess in a large cohort of aSAH patients, during the first week after an intensive care unit (ICU) admission, the incidence of ARDS defined according to the Berlin criteria and its effect on outcome. METHODS: This is a multicentric, retrospective cohort study in 3 European intensive care units. We collected data between January 2009 and December 2017. We included adult patients (≥ 18 years) with a diagnosis of aSAH admitted to the ICU. RESULTS: A total of 855 patients fulfilled the inclusion criteria. ARDS was assessable in 851 patients. The cumulative incidence of ARDS was 2.2% on the first day since ICU admission, 3.2% on day three, and 3.6% on day seven. At the univariate analysis, ARDS was associated with a poor outcome (p = 0.005) at ICU discharge, and at the multivariable analysis, patients with ARDS showed a worse neurological outcome (Odds ratio = 3.00, 95% confidence interval 1.16-7.72; p = 0.023). CONCLUSIONS: ARDS has a low incidence in the first 7 days of ICU stay after aSAH, but it is associated with worse outcome.

International prospective observational study on intracranial pressure in intensive care (ICU): the SYNAPSE-ICU study protocol.

INTRODUCTION: Intracranial pressure (ICP) monitoring is commonly used in neurocritical care patients with acute brain injury (ABI). Practice about indications and use of ICP monitoring in patients with ABI remains, however, highly variable in high-income countries, while data on ICP monitoring in low and middle-income countries are scarce or inconsistent. The aim of the SYNAPSE-ICU study is to describe current practices of ICP monitoring using a worldwide sample and to quantify practice variations in ICP monitoring and management in neurocritical care ABI patients. METHODS AND ANALYSIS: The SYNAPSE-ICU study is a large international, prospective, observational cohort study. From March 2018 to March 2019, all patients fulfilling the following inclusion criteria will be recruited: age >18 years; diagnosis of ABI due to primary haemorrhagic stroke (subarachnoid haemorrhage or intracranial haemorrhage) or traumatic brain injury; Glasgow Coma Score (GCS) with no eye opening (Eyes response=1) and Motor score ≤5 (not following commands) at ICU admission, or neuro-worsening within the first 48 hours with no eye opening and a Motor score decreased to ≤5. Data related to clinical examination (GCS, pupil size and reactivity, Richmond Agitation-Sedation Scale score, neuroimaging) and to ICP interventions (Therapy Intensity Levels) will be recorded on admission, and at day 1, 3 and 7. The Glasgow Outcome Scale Extended (GOSE) will be collected at discharge from ICU and from hospital and at 6-month follow-up. The impact of ICP monitoring and ICP-driven therapy on GOSE will be analysed at both patient and ICU level. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee 'Brianza' at the Azienda Socio Sanitaria Territoriale (ASST)-Monza (approval date: 21 November 2017). Each National Coordinator will notify the relevant ethics committee, in compliance with the local legislation and rules. Data will be made available to the scientific community by means of abstracts submitted to the European Society of Intensive Care Medicine annual conference and by scientific reports and original articles submitted to peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03257904.

A Modified Translaryngeal Tracheostomy Technique in the Neurointensive Care Unit. Rationale and Single-center Experience on 199 Acute Brain-damaged Patients.

BACKGROUND: Brain-injured patients frequently require tracheostomy, but no technique has been shown to be the gold standard for these patients. We developed and introduced into standard clinical practice an innovative bedside translaryngeal tracheostomy (TLT) technique aided by suspension laryngoscopy (modified TLT). During this procedure, the endotracheal tube is left in place until the airway is secured with the new tracheostomy. This study assessed the clinical impact of this technique in brain-injured patients. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data from adult brain-injured patients who had undergone modified TLT during the period spanning from January 2010 to December 2016 at the Neurointensive care unit, San Gerardo Hospital (Monza, Italy). The incidence of intraprocedural complications, including episodes of intracranial hypertension (intracranial pressure [ICP] >20 mm Hg), was documented. Neurological, ventilatory, and hemodynamic parameters were retrieved before, during, and after the procedure. Risk factors for complications and intracranial hypertension were assessed by univariate logistic analysis. Data are presented as n (%) and median (interquartile range) for categorical and continuous variables, respectively. RESULTS: A total of 199 consecutive brain-injured patients receiving modified TLT were included. An overall 52% male individuals who were 66 (54 to 74) years old and who had an admission Glasgow Coma Scale of 7 (6 to 10) were included in the cohort. Intracerebral hemorrhage (30%) was the most frequent diagnosis. Neurointensivists performed 130 (65%) of the procedures. Patients underwent tracheostomy 10 (7 to 13) days after intensive care unit admission. Short (ie, <2 min) and clinically uneventful increases in ICP>20 mm Hg were observed in 11 cases. Overall, the procedure was associated with an increase in ICP from 7 (4 to 10) to 12 (7 to 18) mm Hg (P<0.001). Compared with baseline, cerebral perfusion pressure (CPP), respiratory variables, and hemodynamics were unchanged during the procedure (P-value, not significant). Higher baseline ICP and core temperature were associated with an increased risk of complications and intracranial hypertension. Complication rates were low: 1 procedure had to be converted to a surgical tracheostomy, and 1 (0.5%) episode of minor bleeding and 5 (2.5%) of minor non-neurological complications were recorded. Procedures performed by intensivists did not have a higher risk of complications compared with those performed by ear, nose, and throat specialists. CONCLUSIONS: A modified TLT (by means of suspension laryngoscopy) performed by neurointensivists is feasible in brain-injured patients and does not adversely impact ICP and CPP.

Trajectories of early secondary insults correlate to outcomes of traumatic brain injury: results from a large, single centre, observational study.

BACKGROUND: Secondary insults (SI), such as hypotension, hypoxia, and intracranial hypertension frequently occur after traumatic brain injury (TBI), and have a strong impact on patients' clinical outcomes. The aim of this study is to examine the trajectories of SI from the early phase of injury in the prehospital setting to hospital admission in a cohort of TBI patients. METHODS: This is a retrospective, observational, single centre study on consecutive patients admitted from 1997 to 2016 to the Neuro Intensive Care Unit (NICU) at San Gerardo Hospital, in Monza, Italy. Trajectories of SI from the prehospital to hospital settings were defined as "sustained", "resolved", "new event", and "none". Univariate and multivariate logistic regression analyses were performed to correlate SI trajectories to a 6-months outcome. RESULTS: Nine hundred sixty-seven patients were enrolled in the final analysis. About 20% had hypoxic or hypotensive events and 30.7% of patients had pupillary abnormalities. Hypotension and hypoxia were associated with an unfavourable outcome when "sustained" and "resolved", while pupillary abnormalities were associated with a poor outcome when "sustained" and as "new events". After adjusting for confounding factors, 6-month mortality strongly correlated with "sustained" hypotension (OR 11.25, 95% CI, 3.52-35.99), "sustained" pupillary abnormalities (OR 2.8, 95% CI, 1.51-5.2) and "new event" pupillary abnormalities (OR 2.8, 95% CI, 1.16-6.76). CONCLUSIONS: After TBI, sustained hypotension and pupillary abnormalities are important determinants for patients' outcomes. Early trajectories define the dynamics of SI and contribute to a better understanding of how early recognition and treatments in emergency settings could impact on 6-month outcomes and mortality.

Intracranial pressure monitor insertion in traumatic brain injury: a single center, retrospective decision process analysis.

BACKGROUND: Evidence-based indications for intracranial pressure (ICP) monitoring in patients with traumatic brain injury (TBI) are lacking. The aim of this study was to analyze the main factors that guided the decision-making of invasive ICP monitoring in a large cohort of TBI patients from our institution. METHODS: This is a retrospective, single centre, observational study including adult TBI patients consecutively admitted to our NeuroIntensive Care Unit over 20 years. Logistic regression analyses were performed to identify potential factors associated with the decision for ICP monitor insertion. A decision tree was developed to identify the combination of factors with the highest statistical power to predict the decision for ICP monitor insertion. RESULTS: A total of 857 adult patients were included in the analysis. The decision to monitor ICP was strongly related to different factors, including Glasgow Coma Scale (GCS), Computed Tomography (CT) scan classification, pupils' reactivity, and patients' prognosis at the admission calculated by the International Mission on Prognosis in Traumatic Brain Injury (IMPACT) score (p<0.01). Results from the decision tree showed an overall ability of the 72% in the prediction of ICP monitoring and that, among the factors analysed, CT findings had the primarily and strongest discrimination power. CONCLUSIONS: The decision to insert an invasive ICP monitoring in patients with TBI is multifactorial. Among the different factors analysed in our cohort of TBI patients, prognostication factors as for IMPACT score and in particular CT findings could potentially explain the decision making for ICP monitoring.

Use of brain diffusion tensor imaging for the prediction of long-term neurological outcomes in patients after cardiac arrest: a multicentre, international, prospective, observational, cohort study.

BACKGROUND: Prediction of neurological outcome after cardiac arrest is a major challenge. The aim of this study was to assess whether quantitative whole-brain white matter fractional anisotropy (WWM-FA) measured by diffusion tensor imaging between day 7 and day 28 after cardiac arrest can predict long-term neurological outcome. METHODS: This prospective, observational, cohort study (part of the MRI-COMA study) was done in 14 centres in France, Italy, and Belgium. We enrolled patients aged 18 years or older who had been unconscious for at least 7 days after cardiac arrest into the derivation cohort. The following year, we recruited the validation cohort on the same basis. We also recruited a minimum of five healthy volunteers at each centre for the normalisation procedure. WWM-FA values were compared with standard criteria for unfavourable outcome, conventional MRI sequences (fluid-attenuated inversion recovery and diffusion-weighted imaging), and proton magnetic resonance spectroscopy. The primary outcome was the best achieved Glasgow-Pittsburgh Cerebral Performance Categories (CPC) at 6 months, dichotomised as favourable (CPC 1-2) and unfavourable outcome (CPC 3-5). Prognostication performance was assessed by the area under the receiver operating characteristic (ROC) curves and compared between groups. This study was registered with ClinicalTrials.gov, number NCT00577954. FINDINGS: Between Oct 1, 2006, and June 30, 2014, 185 patients were enrolled in the derivation cohort, of whom 150 had an interpretable multimodal MRI and were included in the analysis. 33 (22%) patients had a favourable neurological outcome at 6 months. Prognostic accuracy, as quantified by the area under the ROC curve, was significantly higher with the normalised WWM-FA value (area under the ROC curve 0·95, 95% CI 0·91-0·98) than with the standard criteria for unfavourable outcome or other MRI sequences. In a subsequent validation cohort of 50 patients (enrolled between April 1, 2015, and March 31, 2016), a normalised WWM-FA value lower than 0·91, set from the derivation cohort, had a negative predictive value of 71·4% (95% CI 41·9-91·6) and a positive predictive value of 100% (90·0-100), with 89·7% sensitivity (75·8-97·1) and 100% specificity (69·1-100) for the prediction of unfavourable outcome. INTERPRETATION: In patients who are unconscious 7 days after cardiac arrest, the normalised WWM-FA value, measured by diffusion tensor imaging, could be used to accurately predict neurological outcome at 6 months. This evidence requires confirmation from future large-scale trials with a strict protocol of withdrawal or limitation-of-care decisions and time window for MRI. FUNDING: French Ministry of Health, French National Agency for Research, Italian Ministry of Health, and Regione Lombardia.

Intracerebral hemorrhage in Intensive Care Unit: early prognostication fallacies. A single center retrospective study.

BACKGROUND: Intracerebral hemorrhage (ICH) admitted to Intensive Care is deem of poor prognosis. The aim of this study was to compare observed and predicted 30-day mortality and to evaluate long term functional outcome in a consecutive ICH cohort. METHODS: Retrospective analysis of prospectively collected data of ICH patients managed in a Neuro-ICU from 2012 to 2015. RESULTS: Out of 136 consecutive patients, 34 (25%) had "withholding of life-sustaining treatment" (WLST) order and 102 (75%) received a "full treatment" (FT). WLST cohort: median (IQR): 72 (70-77) years old, Glasgow Coma Scale (GCS) 4 (3-4) at admission, ICH volume 114 cm3 (68-152); all patients died during neuro-ICU recovery, 28 (82%) patients had brain death diagnosis and 15 (54%) of these were organ donors. FT cohort: 67 (51-73) years old, GCS 9 (6-12) at admission, ICH volume 46 (24-90) cm3, neurosurgery for clot removal in 65 (64%) (P<0.05 vs. WLST cohort for each of previously listed variables); 13 (13%) patients died during neuro-ICU recovery, of these 11 (85%) patients had brain death diagnosis and 4 (36%) of them were organ donors. Overall 30-day observed mortality for FT group was 18% (95% CI: 11-26%). Patients with ICH Score 1, 2, 3, 4+ had 0%, 10%, 16% and 26% 30-day mortality, respectively (P<0.01 vs. ICH Score). Full treatment group 180-day mortality was 32% (95% CI: 24-42%). Modified Rankin Scale (mRS) after one year was ≤3 in 35 (35%), i.e. good recovery, and >3 in 64 (65%). Neurosurgery for clot removal was associated with a lower 30 and 180-day mortality (P=0.01 and P=0.03, respectively) and along with GCS at admission it was an independent significant prognostic factor. CONCLUSIONS: Mortality and functional outcome is less severe than predicted in patients with ICH receiving a full medical and/or surgical treatment.

Organ donation in cardiac arrest patients treated with extracorporeal CPR: A single centre observational study.

AIM OF THE STUDY: In a consecutive cohort of cardiac arrest (CA) treated with extracorporeal cardiopulmonary resuscitation (eCPR), we describe the incidence of brain death (BD), the eligibility for organ donation and the short-term follow-up of the transplanted organs. METHODS: All refractory in- and out-of-hospital CA admitted to our Cardiac Intensive Care Unit between January 2011 and September 2016 treated with eCPR were enrolled in the study. RESULTS: 112 CA patients received eCPR. 82 (73.2%) died in hospital, 25 BD (22.3%) and 57 for other causes (50.9%). At the time of first neurological evaluation after rewarming, variables related to evolution to BD were a lower GCS (3 [3-3] vs. 8 [3-11], p<0.001), a higher level of neuron specific enolase (269.3±49.4 vs. 55.2±37.2ng/ml, p<0.001), a higher presence of EEG indices of poor outcome (84% vs. 15%, p<0.001), absence of brainstem reflexes (p<0.001), absence of bilateral N20 SSEPS waves (66.7% vs. 3.7%, p<0.001). None of BD patients present a normal CT scan (at 2.5±2days), with 85% prevalence of diffuse hypoxic injury and a mean grey/white matter ratio of 1.1±0.1. Rate of donation in BD patients was 56%, with 39 donated organs: 23 kidneys, 12 livers, and 4 lungs. 89.74% of the transplanted organs reached an early good functional recovery. CONCLUSION: In refractory CA patients treated with eCPR, the prevalence of BD is high. This population has a high potential for considering organ donation. Donated organs have a good outcome.

Apnea test during brain death assessment in mechanically ventilated and ECMO patients.

PURPOSE: To evaluate the feasibility and efficacy of an apnea test (AT) technique that combines the application of positive end expiratory pressure (PEEP) with subsequent pulmonary recruitment in a large cohort of brain-dead patients. METHODS: This study was a retrospective analysis of prospectively collected data on brain-dead patients admitted to our institution (Hospital San Gerardo, Monza, Italy) between January 2010 and December 2014. The rate of aborted apnea tests (ATs), occurrence of complications (i.e., pneumothorax, cardiac arrhythmias, cardiac arrest, and severe hypoxia, defined as PaO2 < 40 mmHg), ventilator settings, hemodynamics, and blood gas analyses were evaluated. Subgroup analysis was performed, with patients classified into veno-arterial extracorporeal membrane oxygenation (ECMO) or non-ECMO groups, and into hypoxic (i.e., baseline PaO2/FiO2 < 200 mmHg) and non-hypoxic (i.e., baseline PaO2/FiO2 > 200 mmHg) groups. RESULTS: In total, 169 consecutive patients including 25 on ECMO were included in the study. No AT abortion nor severe complications were detected. The AT was completed in all patients. Fluid boluses and increases or initiation of vasoactive drugs were required in less than 10 and 3% of the AT procedures, respectively. No clinically meaningful alteration in hemodynamics was recorded. Severe hypoxia occurred during 7 (2.4%) and 4 (8%) of the ATs performed in non-ECMO and ECMO patients, respectively (p = 0.063), and it occurred more frequently in hypoxic patients than in non-hypoxic patients (11.1 vs. 4.8%, respectively; p = 0.002). CONCLUSIONS: In a large cohort of consecutive patients, including the largest patient population on ECMO reported to date, our AT technique that combines the application of PEEP with subsequent pulmonary recruitment proved to be feasible and safe.

High-Resolution Intracranial Pressure Burden and Outcome in Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Intracranial pressure (ICP) control is a therapeutic target in patients with aneurysmal subarachnoid hemorrhage, although only a limited number of studies assessed its course and effect on outcome. Pressure-time dose (PTDICP) is a method to quantify the burden and the time spent above a defined threshold of ICP. PTDICP or its relationship with outcome has never been evaluated in aneurysmal subarachnoid hemorrhage. METHODS: Analysis of data prospectively collected from aneurysmal subarachnoid hemorrhage patients admitted to Neurointensive Care Unit. Monitored data, including intraparenchymal ICP, were digitally recorded minute-by-minute in the first 7 days. PTDICP (mm Hg h) was computed using 4 predefined thresholds (15, 20, 25, and 30 mm Hg). Outcome was assessed through Extended Glasgow Outcome Scale at hospital discharge and at 6 months. RESULTS: Fifty-five patients were enrolled. Forty-two patients (76%) presented with a poor clinical grade. Overall, mortality was 17% at hospital discharge and 34% at 6 months. Half of patients required extensive therapy to control high ICP during day 1. Median ICP was 10 mm Hg (4-75), whereas median PTDICP15, PTDICP20, PTDICP25, PTDICP30 were, respectively, 13, 4, 2, and 1 mm Hg h. We observed an association between mortality at hospital discharge and higher level of PTDICP using 20, 25, and 30 mm Hg as thresholds and between exposure to a moderate-level PTDICP30 and unfavorable long-term outcome. CONCLUSIONS: PTDICP may better define one of the insults that the brain suffers after aneurysmal rupture, and exposure to moderate PTDICP30 was significant prognostic factor of 6-month unfavorable outcome.

External Ventricular and Lumbar Drain Device Infections in ICU Patients: A Prospective Multicenter Italian Study.

OBJECTIVE: Use of external ventricular drains and lumbar catheters is associated with a risk of ventriculitis and meningitis ranging from 2% to 24% because of lack of standardized diagnostic criteria. We evaluated the prevalence of ventriculitis or meningitis in 13 Italian ICUs. DESIGN: Multicenter, prospective study. SETTING: Thirteen Italian ICUs. PATIENTS: Two hundred seventy-one patients (mean age, 57 yr) receiving a total number of 311 catheters. Two hundred fifty patients (92.2%) had an external ventricular drain, 17 patients (6.3%) had a lumbar catheter, and four patients (1.5%) had both external ventricular drain and lumbar catheter. INTERVENTIONS: ICUs enrolled at least 10 consecutive adult patients with an external ventricular drain or lumbar catheter in place for more than 24 hours. Confirmed cerebrospinal fluid infection was defined by presence of a positive cerebrospinal fluid culture, a cerebrospinal fluid/blood glucose ratio less than 0.5, a neutrophilic cerebrospinal fluid pleocytosis (> 5 cells/µL), and fever. Abnormal cerebrospinal fluid findings with negative cultures were defined as suspected infection. MEASUREMENTS AND MAIN RESULTS: Median duration of device use was 13 days (interquartile range, 8-19). Fifteen patients (5.5%) had a confirmed ventriculitis or meningitis, and 15 patients (5.5%) had a suspected ventriculitis or meningitis. Cerebrospinal fluid glucose and cerebrospinal fluid/blood glucose ratio were lower in patients with confirmed ventriculitis or meningitis and suspected ventriculitis or meningitis; proteins and lactates were significantly higher in confirmed ventriculitis or meningitis. Gram-negative and Gram-positive bacteria were equally cultured. Risk factors for infection were a concomitant extracranial infection (odds ratio, 2.34; 95% CI, 1.01-5.40; p = 0.05) and placement of catheters outside the operation room (odds ratio, 4.01; 95% CI, 0.98-16.50; p = 0.05). CONCLUSIONS: Ventriculitis or meningitis remains a problem in Italian ICUs, and a strategy for reducing the prevalence is worth planning.

Variability in brain death determination in europe: looking for a solution.

BACKGROUND: Criteria for determining brain death (BD) vary between countries. We report the results of an investigation designed to compare procedures to determine BD in different European countries. METHODS: We developed a web-based questionnaire that was sent to representatives of 33 European countries. Responses were reviewed, and individual respondents were contacted if clarification was required. RESULTS: Responses were received from 28 (85 %) of the 33 countries to which the questionnaire was sent. Each country has either a law (93 %) or national guidance (89 %) for defining BD. Clinical examination is sufficient to determine BD in 50 % of countries; coma, apnea, absence of corneal, and cough reflexes are mandatory criteria in all. Confirmation of apnea is required in all countries but not defined in 4 (14 %). In the 24 (86 %) of countries with a formal definition of the apnea test, a target pCO2 level (23/24, 96 %) is the pre-specified end point in most. The (median, range) number of clinical examinations (2, 1-3) and minimum observation time between tests (3 h, 0-12 h) vary greatly between countries. Additional (confirmatory) tests are required in 50 % of countries. Hypothermia (4 %), anoxic injury (7 %), inability to complete clinical examination (61 %), toxic drug levels (57 %), and inconclusive apnea test (54 %) are among the most common indications for confirmatory tests. Cerebral blood flow (CBF) investigation is mandatory in 18 % of countries, but optional or indicated only in selected cases in 82 %. Conventional angiography is the preferred method of determining absent CBF (50 %), followed by transcranial Doppler sonography (43 %), computerized tomography (CT) angiography (39 %), CT perfusion, and magnetic resonance imaging (MRI) angiography (11 %). Electroencephalography is always (21 %) or optionally (14 %) recorded. CONCLUSIONS: Although legislation or professional guidance is available to standardize nationally the BD diagnosis process in all European countries, there are still disparities between countries. The current variation in practice makes an international consensus for the definition of BD imperative.

Diet induced mild hypercholesterolemia in pigs: local and systemic inflammation, effects on vascular injury - rescue by high-dose statin treatment.

OBJECTIVE: The aim of the present study was to comprehensively evaluate systemic and local inflammation as well as progression of vascular inflammation in normal and mechanically injured vessels in a large animal model of mild hypercholesterolemia. Our aim was also to test the effect of high-dose statin treatment on these processes. METHODS: Pigs were kept for 120 days on a standard diet (SD, n=7), high-cholesterol diet (HCD, n=7) or high-cholesterol diet with Atorvastatin starting after 50 days (STATIN, n=7). Left carotid artery balloon injury was conducted in all groups after 60 days of diet treatment. Biochemical analysis together with evaluation of blood and tissue markers of vascular injury and inflammation were performed in all groups at the end of experiment. RESULTS: HCD compared to SD induced systemic inflammation demonstrated by increased number of circulating monocytes and lymphocytes. HCD compared to SD induced also local inflammation demonstrated by adipocyte hypertrophy and infiltration of T-lymphocytes in abdominal white adipose tissue, activation of hepatic stellate cells with infiltration of T- and B-lymphocytes and macrophages in the liver and increased macrophage content in lung parenchyma. These changes were accompanied by increased Intima/Media thickness, stenosis, matrix deposition and activated T-cell infiltrates in injured but not in uninjured contralateral carotid artery as we previously reported. The treatment with high-dose statin attenuated all aspects of systemic and local inflammation as well as pathological changes in injured carotid artery. CONCLUSIONS: Diet related mild hypercholesterolemia induce systemic and local inflammation in the liver, lung and adipose tissue that coincide with enhanced inflammation of injured vessel but is without deleterious effect on uninjured vessels. High dose statin attenuated systemic and local inflammation and protected injured vessels. However, finding exact role of reduced systemic and remote inflammation in vascular protection requires further studies.

Genetically modified pigs produced with a nonviral episomal vector.

Genetic modification of cells and animals is an invaluable tool for biotechnology and biomedicine. Currently, integrating vectors are used for this purpose. These vectors, however, may lead to insertional mutagenesis and variable transgene expression and can undergo silencing. Scaffold/matrix attachment region-based vectors are nonviral expression systems that replicate autonomously in mammalian cells, thereby making possible safe and reliable genetic modification of higher eukaryotic cells and organisms. In this study, genetically modified pig fetuses were produced with the scaffold/matrix attachment region-based vector pEPI, delivered to embryos by the sperm-mediated gene transfer method. The pEPI vector was detected in 12 of 18 fetuses in the different tissues analyzed and was shown to be retained as an episome. The reporter gene encoded by the pEPI vector was expressed in 9 of 12 genetically modified fetuses. In positive animals, all tissues analyzed expressed the reporter gene; moreover in these tissues, the positive cells were on the average 79%. The high percentage of EGFP-expressing cells and the absence of mosaicism have important implications for biotechnological and biomedical applications. These results are an important step forward in animal transgenesis and can provide the basis for the future development of germ-line gene therapy.