Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI.

BACKGROUND: Traumatic brain injury (TBI) is associated with the tauopathies Alzheimer's disease and chronic traumatic encephalopathy. Advanced immunoassays show significant elevations in plasma total tau (t-tau) early post-TBI, but concentrations subsequently normalise rapidly. Tau phosphorylated at serine-181 (p-tau181) is a well-validated Alzheimer's disease marker that could potentially seed progressive neurodegeneration. We tested whether post-traumatic p-tau181 concentrations are elevated and relate to progressive brain atrophy. METHODS: Plasma p-tau181 and other post-traumatic biomarkers, including total-tau (t-tau), neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), were assessed after moderate-to-severe TBI in the BIO-AX-TBI cohort (first sample mean 2.7 days, second sample within 10 days, then 6 weeks, 6 months and 12 months, n=42). Brain atrophy rates were assessed in aligned serial MRI (n=40). Concentrations were compared patients with and without Alzheimer's disease, with healthy controls. RESULTS: Plasma p-tau181 concentrations were significantly raised in patients with Alzheimer's disease but not after TBI, where concentrations were non-elevated, and remained stable over one year. P-tau181 after TBI was not predictive of brain atrophy rates in either grey or white matter. In contrast, substantial trauma-associated elevations in t-tau, NfL, GFAP and UCH-L1 were seen, with concentrations of NfL and t-tau predictive of brain atrophy rates. CONCLUSIONS: Plasma p-tau181 is not significantly elevated during the first year after moderate-to-severe TBI and levels do not relate to neuroimaging measures of neurodegeneration.

Investigating the characteristics and correlates of systemic inflammation after traumatic brain injury: the TBI-BraINFLAMM study.

INTRODUCTION: A significant environmental risk factor for neurodegenerative disease is traumatic brain injury (TBI). However, it is not clear how TBI results in ongoing chronic neurodegeneration. Animal studies show that systemic inflammation is signalled to the brain. This can result in sustained and aggressive microglial activation, which in turn is associated with widespread neurodegeneration. We aim to evaluate systemic inflammation as a mediator of ongoing neurodegeneration after TBI. METHODS AND ANALYSIS: TBI-braINFLAMM will combine data already collected from two large prospective TBI studies. The CREACTIVE study, a broad consortium which enrolled >8000 patients with TBI to have CT scans and blood samples in the hyperacute period, has data available from 854 patients. The BIO-AX-TBI study recruited 311 patients to have acute CT scans, longitudinal blood samples and longitudinal MRI brain scans. The BIO-AX-TBI study also has data from 102 healthy and 24 non-TBI trauma controls, comprising blood samples (both control groups) and MRI scans (healthy controls only). All blood samples from BIO-AX-TBI and CREACTIVE have already been tested for neuronal injury markers (GFAP, tau and NfL), and CREACTIVE blood samples have been tested for inflammatory cytokines. We will additionally test inflammatory cytokine levels from the already collected longitudinal blood samples in the BIO-AX-TBI study, as well as matched microdialysate and blood samples taken during the acute period from a subgroup of patients with TBI (n=18).We will use this unique dataset to characterise post-TBI systemic inflammation, and its relationships with injury severity and ongoing neurodegeneration. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the London-Camberwell St Giles Research Ethics Committee (17/LO/2066). Results will be submitted for publication in peer-review journals, presented at conferences and inform the design of larger observational and experimental medicine studies assessing the role and management of post-TBI systemic inflammation.

Thoracic UltrasONOgraphy Reporting: The TUONO Consensus.

The widespread use of the lung ultrasound (LUS) has not been followed by the development of a comprehensive standardized tool for its reporting in the intensive care unit (ICU) which could be useful to promote consistency and reproducibility during clinical examination. This work aims to define the essential features to be included in a standardized reporting tool and provides a structured model form to fully express the diagnostic potential of LUS and facilitate intensivists in the use of a LUS in everyday clinical ICU examination. We conducted a modified Delphi process to build consensus on the items to be integrated in a standardized report form and on its structure. A committee of 19 critical care physicians from 19 participating ICUs in Italy was formed, including intensivists experienced in ultrasound from both teaching hospitals and referral hospitals, and internationally renowned experts on the LUS. The consensus for 31 statements out of 33 was reached at the third Delphi round. A structured model form was developed based on the approved statements. The development of a standardized model as a backbone to report a LUS may facilitate the guidelines' application in clinical practice and increase inter-operator agreement. Further studies are needed to evaluate the effects of standardized reports in critically ill patients.

Thoracic UltrasONOgraphy Reporting: The TUONO Study.

Lung ultrasound (LUS) is a validated technique for the prompt diagnosis and bedside monitoring of critically ill patients due to its availability, safety profile, and cost-effectiveness. The aim of this work is to detect similarities and differences among LUS reports performed in ICUs and to provide a common ground for an integrated report form. We collected all LUS reports during an index week in 21 ICUs from the GiViTI network. First, we considered signs, chest areas, and terminology reported. Then, we compared different report structures and categorized them as structured reports (SRs), provided with a predefined model form, and free unstructured text reports (FTRs) that had no predetermined structure. We analyzed 171 reports from 21 ICUs, and 59 reports from 5 ICUs were structured. All the reports presented a qualitative description that mainly focused on the presence of B-lines, consolidations, and pleural effusion. Zones were defined in 66 reports (39%). In SRs, a complete examination of all the regions was more frequently achieved (96% vs. 74%), and a higher impact on therapeutic strategies was observed (17% vs. 6%). LUS reports vary significantly among different centers. Adopting an integrated SR seems to promote a systematic approach in scanning and reporting, with a potential impact on LUS clinical applications.

Effectiveness of a Multifaced Antibiotic Stewardship Program: A Pre-Post Study in Seven Italian ICUs.

Multidrug resistance has become a serious threat for health, particularly in hospital-acquired infections. To improve patients' safety and outcomes while maintaining the efficacy of antimicrobials, complex interventions are needed involving infection control and appropriate pharmacological treatments in antibiotic stewardship programs. We conducted a multicenter pre-post study to assess the impact of a stewardship program in seven Italian intensive care units (ICUs). Each ICU was visited by a multidisciplinary team involving clinicians, microbiologists, pharmacologists, infectious disease specialists, and data scientists. Interventions were targeted according to the characteristics of each unit. The effect of the program was measured with a panel of indicators computed with data from the MargheritaTre electronic health record. The median duration of empirical therapy decreased from 5.6 to 4.6 days and the use of quinolones dropped from 15.3% to 6%, both p < 0.001. The proportion of multi-drug-resistant bacteria (MDR) in ICU-acquired infections fell from 57.7% to 48.8%. ICU mortality and length of stay remained unchanged, indicating that reducing antibiotic administration did not harm patients' safety. This study shows that our stewardship program successfully improved the management of infections. This suggests that policy makers should tackle multidrug resistance with a multidisciplinary approach based on continuous monitoring and personalised interventions.

Benchmark of Intraoperative Activity in Cardiac Surgery: A Comparison between Pre- and Post-Operative Prognostic Models.

OBJECTIVES: Despite its large diffusion and improvements in safety, the risks of complications after cardiac surgery remain high. Published predictive perioperative scores (EUROSCORE, STS, ACEF) assess risk on preoperative data only, not accounting for the intraopertive period. We propose a double-fold model, including data collected before surgery and data collected at the end of surgery, to evaluate patient risk evolution over time and assess the direct contribution of surgery. METHODS: A total of 15,882 cardiac surgery patients from a Margherita-Prosafe cohort study were included in the analysis. Probability of death was estimated using two logistic regression models (preoperative data only vs. post-operative data, also including information at discharge from the operatory theatre), testing calibration and discrimination of each model. RESULTS: Pre-operative and post-operative models were built and demonstrate good discrimination and calibration with AUC = 0.81 and 0.87, respectively. Relative difference in pre- and post-operative mortality in separate centers ranged from -0.36 (95% CI: -0.44--0.28) to 0.58 (95% CI: 0.46-0.71). The usefulness of this two-fold preoperative model to benchmark medical care in single hospital is exemplified in four cases. CONCLUSIONS: Predicted post-operative mortality differs from predicted pre-operative mortality, and the distance between the two models represent the impact of surgery on patient outcomes. A double-fold model can assess the impact of the intra-operative team and the evolution of patient risk over time, and benchmark different hospitals on patients subgroups to promote an improvement in medical care in each center.

High dose coupled plasma filtration and adsorption in septic shock patients. Results of the COMPACT-2: a multicentre, adaptive, randomised clinical trial.

PURPOSE: This study aimed at evaluating the efficacy and safety of high-dose (> 0.2 L/kg of treated plasma per day) coupled plasma filtration-adsorption (CPFA) in treating patients with septic shock. METHODS: Multicentre, randomised, adaptive trial, performed in 12 Italian intensive care units (ICUs). Patients aged 14 or more, admitted to the ICU with septic shock, or had developed it during the stay were eligible. The final outcome was mortality at discharge from the last hospital at which the patient received care. RESULTS: Between May 2015, and October 2017, 115 patients were randomised. The first interim analysis revealed a number of early deaths, prompting an unplanned analysis. Last hospital mortality was non-significantly higher in the CPFA (55.6%) than in the control group (46.2%, p = 0.35). The 90-day survival curves diverged in favour of the controls early after randomisation and remained separated afterwards (p = 0.100). An unplanned analysis showed higher mortality in CPFA compared to controls among patients without severe renal failure (p = 0.025); a dose-response relationship was observed between treated plasma volume and mortality (p = 0.010). CONCLUSION: The COMPACT-2 trial was stopped due to the possible harmful effect of CPFA in patients with septic shock. The harmful effect, if present, was particularly marked in the early phase of septic shock. Patients not requiring renal replacement therapy seemed most exposed to the possible harm, with evidence of a dose-response effect. Until the mechanisms behind these results are fully understood, the use of CPFA for the treatment of patients with septic shock is not recommended.

Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury.

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.

PROSAFE: a European endeavor to improve quality of critical care medicine in seven countries.

BACKGROUND: Long-lasting shared research databases are an important source of epidemiological information and can promote comparison between different healthcare services. Here we present PROSAFE, an advanced international research network in intensive care medicine, with the focus on assessing and improving the quality of care. The project involved 343 ICUs in seven countries. All patients admitted to the ICU were eligible for data collection. METHODS: The PROSAFE network collected data using the same electronic case report form translated into the corresponding languages. A complex, multidimensional validation system was implemented to ensure maximum data quality. Individual and aggregate reports by country, region, and ICU type were prepared annually. A web-based data-sharing system allowed participants to autonomously perform different analyses on both own data and the entire database. RESULTS: The final analysis was restricted to 262 general ICUs and 432,223 adult patients, mostly admitted to Italian units, where a research network had been active since 1991. Organization of critical care medicine in the seven countries was relatively similar, in terms of staffing, case mix and procedures, suggesting a common understanding of the role of critical care medicine. Conversely, ICU equipment differed, and patient outcomes showed wide variations among countries. CONCLUSIONS: PROSAFE is a permanent, stable, open access, multilingual database for clinical benchmarking, ICU self-evaluation and research within and across countries, which offers a unique opportunity to improve the quality of critical care. Its entry into routine clinical practice on a voluntary basis is testimony to the success and viability of the endeavor.

Multicentre longitudinal study of fluid and neuroimaging BIOmarkers of AXonal injury after traumatic brain injury: the BIO-AX-TBI study protocol.

INTRODUCTION AND AIMS: Traumatic brain injury (TBI) often results in persistent disability, due particularly to cognitive impairments. Outcomes remain difficult to predict but appear to relate to axonal injury. Several new approaches involving fluid and neuroimaging biomarkers show promise to sensitively quantify axonal injury. By assessing these longitudinally in a large cohort, we aim both to improve our understanding of the pathophysiology of TBI, and provide better tools to predict clinical outcome. METHODS AND ANALYSIS: BIOmarkers of AXonal injury after TBI is a prospective longitudinal study of fluid and neuroimaging biomarkers of axonal injury after moderate-to-severe TBI, currently being conducted across multiple European centres. We will provide a detailed characterisation of axonal injury after TBI, using fluid (such as plasma/microdialysate neurofilament light) and neuroimaging biomarkers (including diffusion tensor MRI), which will then be related to detailed clinical, cognitive and functional outcome measures. We aim to recruit at least 250 patients, including 40 with cerebral microdialysis performed, with serial assessments performed twice in the first 10 days after injury, subacutely at 10 days to 6 weeks, at 6 and 12 months after injury. ETHICS AND DISSEMINATION: The relevant ethical approvals have been granted by the following ethics committees: in London, by the Camberwell St Giles Research Ethics Committee; in Policlinico (Milan), by the Comitato Etico Milano Area 2; in Niguarda (Milan), by the Comitato Etico Milano Area 3; in Careggi (Florence), by the Comitato Etico Regionale per la Sperimentazione Clinica della Regione Toscana, Sezione area vasta centro; in Trento, by the Trento Comitato Etico per le Sperimentazioni Cliniche, Azienda Provinciale per i Servizi Sanitari della Provincia autonoma di Trento; in Lausanne, by the Commission cantonale d'éthique de la recherche sur l'être humain; in Ljubljana, by the National Medical Ethics Committee at the Ministry of Health of the Republic of Slovenia. The study findings will be disseminated to patients, healthcare professionals, academics and policy-makers including through presentation at conferences and peer-reviewed publications. Data will be shared with approved researchers to provide further insights for patient benefit. TRIAL REGISTRATION NUMBER: NCT03534154.

Data collection and research with MargheritaTre.

OBJECTIVE: MargheritaTre is an electronic health record developed by the Italian Group for the Evaluation of Interventions in Intensive Care Medicine designed to support clinical practice in intensive care units (ICUs) and ensure high-quality data for research purposes. APPROACH: MargheritaTre was developed in collaboration with clinical experts, researchers, and IT specialists. It is currently installed in 40 ICUs and its database contains complete records of more than 65,000 patients. To facilitate data analysis, information is mostly stored in structured or partially structured form. MAIN RESULTS: Data collected with MargheritaTre allow one to conduct research studies on complex clinical problems from manifold perspectives and with different levels of detail, such as epidemiological studies, analyses of the process of care and physiopathological investigations, at both single-organ and organism level. In this paper we describe some of the first projects based on this electronic health record to illustrate its potential for research. SIGNIFICANCE: The MargheritaTre database is a huge and rapidly growing mine of data that will be exploited by our laboratory and shared with other groups to address complex and innovative research and clinical questions. The ultimate aim of these projects is the improvement of the quality of care and patient outcomes, through the development of expert systems integrated in the electronic health record to support clinical practice.

The Hematocrit Affects the Volume of Plasma Treated With Coupled Plasma Filtration and Adsorption With Predilution.

Coupled plasma filtration and adsorption (CPFA) is an extracorporeal blood purification technique proposed for the treatment of septic-shock. By removing pro- and anti-inflammatory mediators from plasma, CPFA is supposed to have a therapeutic effect on the abnormal inflammatory response seen in this condition. Recently, blood predilution with citrate solution has been adopted to prevent clotting in the CPFA circuit-one of the main problems of the technique. Taking into account the patient's hematocrit, we worked out a formula for the volume of plasma effectively treated by CPFA after predilution. Neglecting this effect, as is commonly done, introduces significant distortions in the estimation of the volume, possibly causing under-treatment. The distortion is stronger when the hematocrit and the predilution fraction are large and weaker when both values shrink. By correctly indicating the daily dose of plasma adsorption received by patients, this formula is essential for assessing the therapeutic efficacy of CPFA and, subsequently, establishing its optimal doses.