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1.
J Neurol Neurosurg Psychiatry ; 95(4): 356-359, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-37833041

RESUMO

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.


Assuntos
Doença de Alzheimer , Lesões Encefálicas Traumáticas , Encefalopatia Traumática Crônica , Humanos , Biomarcadores , Proteínas tau , Imageamento por Ressonância Magnética , Ubiquitina Tiolesterase , Atrofia , Peptídeos beta-Amiloides
2.
BMJ Open ; 13(5): e069594, 2023 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-37221026

RESUMO

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.


Assuntos
Lesões Encefálicas Traumáticas , Doenças Neurodegenerativas , Animais , Estudos Prospectivos , Encéfalo , Citocinas , Inflamação
3.
Artigo em Inglês | MEDLINE | ID: mdl-37107786

RESUMO

Purpose: To assess the prevalence of symptoms of Post-Traumatic Stress Disorder (PTSD) in survivors of COVID-19 Acute Respiratory Distress Syndrome that needed ICU care; to investigate risk factors and their impact on the Health-Related Quality of life (HR-QoL). Materials and Methods: This multicenter, prospective, observational study included all patients who were discharged from the ICU. Patients were administered the European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) questionnaire, the Short-Form Health Survey 36Version 2 (SF-36v2), a socioeconomic question set and the Impact of Event Scale-Revised (IES-R) to assess PTSD. Results: The multivariate logistic regression model found that an International Standard Classification of Education Score (ISCED) higher than 2 (OR 3.42 (95% CI 1.28-9.85)), monthly income less than EUR 1500 (OR 0.36 (95% CI 0.13-0.97)), and more than two comorbidities (OR 4.62 (95% CI 1.33-16.88)) are risk factors for developing PTSD symptoms. Patients with PTSD symptoms are more likely to present a worsening in their quality of life as assessed by EQ-5D-5L and SF-36 scales. Conclusion: The main factors associated with the development of PTSD-related symptoms were a higher education level, a lower monthly income, and more than two comorbidities. Patients who developed symptoms of PTSD reported a significantly lower Health-Related Quality of life as compared to patients without PTSD. Future research areas should be oriented toward recognizing potential psychosocial and psychopathological variables capable of influencing the quality of life of patients discharged from the intensive care unit to better recognize the prognosis and longtime effects of diseases.


Assuntos
COVID-19 , Síndrome do Desconforto Respiratório , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Qualidade de Vida/psicologia , Estudos Prospectivos , Incidência , COVID-19/epidemiologia , COVID-19/complicações , Unidades de Terapia Intensiva , Sobreviventes/psicologia , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/etiologia , Fatores de Risco
4.
J Clin Med ; 12(3)2023 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-36769705

RESUMO

BACKGROUND: Investigating the health-related quality of life (HRQoL) after intensive care unit (ICU) discharge is necessary to identify possible modifiable risk factors. The primary aim of this study was to investigate the HRQoL in COVID-19 critically ill patients one year after ICU discharge. METHODS: In this multicenter prospective observational study, COVID-19 patients admitted to nine ICUs from 1 March 2020 to 28 February 2021 in Italy were enrolled. One year after ICU discharge, patients were required to fill in short-form health survey 36 (SF-36) and impact of event-revised (IES-R) questionnaire. A multivariate linear or logistic regression analysis to search for factors associated with a lower HRQoL and post-traumatic stress disorded (PTSD) were carried out, respectively. RESULTS: Among 1003 patients screened, 343 (median age 63 years [57-70]) were enrolled. Mechanical ventilation lasted for a median of 10 days [2-20]. Physical functioning (PF 85 [60-95]), physical role (PR 75 [0-100]), emotional role (RE 100 [33-100]), bodily pain (BP 77.5 [45-100]), social functioning (SF 75 [50-100]), general health (GH 55 [35-72]), vitality (VT 55 [40-70]), mental health (MH 68 [52-84]) and health change (HC 50 [25-75]) describe the SF-36 items. A median physical component summary (PCS) and mental component summary (MCS) scores were 45.9 (36.5-53.5) and 51.7 (48.8-54.3), respectively, considering 50 as the normal value of the healthy general population. In all, 109 patients (31.8%) tested positive for post-traumatic stress disorder, also reporting a significantly worse HRQoL in all SF-36 domains. The female gender, history of cardiovascular disease, liver disease and length of hospital stay negatively affected the HRQoL. Weight at follow-up was a risk factor for PTSD (OR 1.02, p = 0.03). CONCLUSIONS: The HRQoL in COVID-19 ARDS (C-ARDS) patients was reduced regarding the PCS, while the median MCS value was slightly above normal. Some risk factors for a lower HRQoL have been identified, the presence of PTSD is one of them. Further research is warranted to better identify the possible factors affecting the HRQoL in C-ARDS.

5.
J Neurotrauma ; 40(5-6): 472-481, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36193562

RESUMO

Following traumatic brain injury (TBI), cerebral metabolic dysfunction, characterized by an elevated cerebral microdialysis (CMD) lactate/pyruvate (LP) ratio, is associated with poor outcome. However, the exact pathophysiological mechanisms underlying this association are not entirely established. In this pre-planned analysis of the BIOmarkers of AXonal injury after Traumatic Brain Injury (BIO-AX-TBI) prospective study, we investigated any associations of LP ratio with brain structure volume change rates at 1 year. Fourteen subjects underwent acute-phase (0-96 h post-TBI) CMD monitoring and had longitudinal magnetic resonance imaging (MRI) quantification of brain volume loss between the subacute phase (14 days to 6 weeks) and 1 year after TBI, recalculated as an annual rate. On average, CMD showed an elevated (>25) LP ratio (31 [interquartile range (IQR) 24-34]), indicating acute cerebral metabolic dysfunction. Annualized whole brain and total gray matter (GM) volume change rates were abnormally reduced (-3.2% [-9.3 to -2.2] and -1.9% [-4.4 to 1.7], respectively). Reduced annualized total GM volume correlated significantly with elevated CMD LP ratio (Spearman's ρ = -0.68, p-value = 0.01) and low CMD glucose (ρ = 0.66, p-value = 0.01). After adjusting for age, admission Glasgow Coma Scale (GCS) score and CT Marshall score, CMD LP ratio remained strongly associated with 1-year total GM volume change rate (p < 0.001; multi-variable analysis). No relationship was found between WM volume changes and CMD metabolites. We demonstrate a strong association between acute post-traumatic cerebral metabolic dysfunction and 1-year gray matter atrophy, reinforcing the role of CMD LP ratio as an early biomarker of poor long-term recovery after TBI.


Assuntos
Encefalopatias , Lesões Encefálicas Traumáticas , Humanos , Estudos Prospectivos , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Escala de Coma de Glasgow , Biomarcadores
6.
Crit Care ; 26(1): 277, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36100903

RESUMO

BACKGROUND: Recent reports of patients with severe, late-stage COVID-19 ARDS with reduced respiratory system compliance described paradoxical decreases in plateau pressure and increases in respiratory system compliance in response to anterior chest wall loading. We aimed to assess the effect of chest wall loading during supine and prone position in ill patients with COVID-19-related ARDS and to investigate the effect of a low or normal baseline respiratory system compliance on the findings. METHODS: This is a single-center, prospective, cohort study in the intensive care unit of a COVID-19 referral center. Consecutive mechanically ventilated, critically ill patients with COVID-19-related ARDS were enrolled and classified as higher (≥ 40 ml/cmH2O) or lower respiratory system compliance (< 40 ml/cmH2O). The study included four steps, each lasting 6 h: Step 1, supine position, Step 2, 10-kg continuous chest wall compression (supine + weight), Step 3, prone position, Step 4, 10-kg continuous chest wall compression (prone + weight). The mechanical properties of the respiratory system, gas exchange and alveolar dead space were measured at the end of each step. RESULTS: Totally, 40 patients were enrolled. In the whole cohort, neither oxygenation nor respiratory system compliance changed between supine and supine + weight; both increased during prone positioning and were unaffected by chest wall loading in the prone position. Alveolar dead space was unchanged during all the steps. In 16 patients with reduced compliance, PaO2/FiO2 significantly increased from supine to supine + weight and further with prone and prone + weight (107 ± 15.4 vs. 120 ± 18.5 vs. 146 ± 27.0 vs. 159 ± 30.4, respectively; p < 0.001); alveolar dead space decreased from both supine and prone position after chest wall loading, and respiratory system compliance significantly increased from supine to supine + weight and from prone to prone + weight (23.9 ± 3.5 vs. 30.9 ± 5.7 and 31.1 ± 5.7 vs. 37.8 ± 8.7 ml/cmH2O, p < 0.001). The improvement was higher the lower the baseline compliance. CONCLUSIONS: Unlike prone positioning, chest wall loading had no effects on respiratory system compliance, gas exchange or alveolar dead space in an unselected cohort of critically ill patients with C-ARDS. Only patients with a low respiratory system compliance experienced an improvement, with a higher response the lower the baseline compliance.


Assuntos
COVID-19 , Síndrome do Desconforto Respiratório , Parede Torácica , Estudos de Coortes , Estado Terminal/terapia , Humanos , Decúbito Ventral/fisiologia , Estudos Prospectivos , Síndrome do Desconforto Respiratório/terapia , Mecânica Respiratória/fisiologia
7.
J Clin Monit Comput ; 36(2): 461-471, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33635495

RESUMO

PURPOSE: The COVID-19-related shortage of ICU beds magnified the need of tools to properly titrate the ventilator assistance. We investigated whether bedside-available indices such as the ultrasonographic changes in diaphragm thickening ratio (TR) and the tidal swing in central venous pressure (ΔCVP) are reliable estimates of inspiratory effort, assessed as the tidal swing in esophageal pressure (ΔPes). METHODS: Prospective, observational clinical investigation in the intensive care unit of a tertiary care Hospital. Fourteen critically-ill patients were enrolled (age 64 ± 7 years, BMI 29 ± 4 kg/m2), after 6 [3; 9] days from onset of assisted ventilation. A three-level pressure support trial was performed, at 10 (PS10), 5 (PS5) and 0 cmH2O (PS0). In each step, the esophageal and central venous pressure tidal swing were recorded, as well as diaphragm ultrasound. RESULTS: The reduction of pressure support was associated with an increased respiratory rate and a reduced tidal volume, while minute ventilation was unchanged. ΔPes significantly increased with reducing support (5 [3; 8] vs. 8 [14; 13] vs. 12 [6; 16] cmH2O, p < 0.0001), as did the diaphragm TR (9.2 ± 6.1 vs. 17.6 ± 7.2 vs. 28.0 ± 10.0%, p < 0.0001) and the ΔCVP (4 [3; 7] vs. 8 [5; 9] vs. 10 [7; 11] cmH2O, p < 0.0001). ΔCVP was significantly associated with ΔPes (R2 = 0.810, p < 0.001), as was diaphragm TR, albeit with a lower coefficient of determination (R2 = 0.399, p < 0.001). CONCLUSIONS: In patients with COVID-19-associated respiratory failure undergoing assisted mechanical ventilation, ΔCVP is a better estimate of inspiratory effort than diaphragm ultrasound.


Assuntos
COVID-19 , Diafragma , Idoso , Pressão Venosa Central , Diafragma/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Respiração com Pressão Positiva , Estudos Prospectivos , Respiração Artificial
8.
J Anesth Analg Crit Care ; 2(1): 20, 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-37386529

RESUMO

PURPOSE: Assess long-term quality of life (HR-QoL) and socio-economic impact in COVID-19-related ARDS (C-ARDS) survivors. METHODS: C-ARDS survivors were followed up at 6 months in this prospective, cohort study. HR-QoL was assessed using SF-36 and EQ-5D-5L, and the socio-economic burden of COVID-19 was evaluated with a dedicated questionnaire. Clinical data were prospectively recorded. RESULTS: Seventy-nine survivors, age 63 [57-71], 84% male, were enrolled. The frequency of EQ-5D-5L reported problems was significantly higher among survivors compared to normal, in mobility, usual activities, and self-care; anxiety and depression and pain were not different. SF-36 scores were lower than the reference population, and physical and mental summary scores were below normal in 52% and 33% of the subjects, respectively. In the multivariable analysis, prolonged hospital length of stay (OR 1.45; p 0.02) and two or more comorbidities on admission (OR 7.42; p 0.002) were significant predictors of impaired "physical" and "mental" HR-QoL, respectively. A total of 38% subjects worsened social relations, 42% changed their employment status, and 23% required personal care support. CONCLUSIONS: C-ARDS survivors have long-term impairment in HR-QoL and socio-economic problems. Prolonged hospital stay and previous comorbidities are risk factors for developing health-related issues.

10.
Sci Transl Med ; 13(613): eabg9922, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34586833

RESUMO

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.


Assuntos
Lesões Encefálicas Traumáticas , Filamentos Intermediários , Axônios , Biomarcadores , Encéfalo , Lesões Encefálicas Traumáticas/complicações , Humanos
11.
Crit Care ; 25(1): 155, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888132

RESUMO

INTRODUCTION: Critical illness from SARS-CoV-2 infection (COVID-19) is associated with a high burden of pulmonary embolism (PE) and thromboembolic events despite standard thromboprophylaxis. Available guidance is discordant, ranging from standard care to the use of therapeutic anticoagulation for enhanced thromboprophylaxis (ET). Local ET protocols have been empirically determined and are generally intermediate between standard prophylaxis and full anticoagulation. Concerns have been raised in regard to the potential risk of haemorrhage associated with therapeutic anticoagulation. This report describes the prevalence and safety of ET strategies in European Intensive Care Unit (ICUs) and their association with outcomes during the first wave of the COVID pandemic, with particular focus on haemorrhagic complications and ICU mortality. METHODS: Retrospective, observational, multi-centre study including adult critically ill COVID-19 patients. Anonymised data included demographics, clinical characteristics, thromboprophylaxis and/or anticoagulation treatment. Critical haemorrhage was defined as intracranial haemorrhage or bleeding requiring red blood cells transfusion. Survival was collected at ICU discharge. A multivariable mixed effects generalised linear model analysis matched for the propensity for receiving ET was constructed for both ICU mortality and critical haemorrhage. RESULTS: A total of 852 (79% male, age 66 [37-85] years) patients were included from 28 ICUs. Median body mass index and ICU length of stay were 27.7 (25.1-30.7) Kg/m2 and 13 (7-22) days, respectively. Thromboembolic events were reported in 146 patients (17.1%), of those 78 (9.2%) were PE. ICU mortality occurred in 335/852 (39.3%) patients. ET was used in 274 (32.1%) patients, and it was independently associated with significant reduction in ICU mortality (log odds = 0.64 [95% CIs 0.18-1.1; p = 0.0069]) but not an increased risk of critical haemorrhage (log odds = 0.187 [95%CI - 0.591 to - 0.964; p = 0.64]). CONCLUSIONS: In a cohort of critically ill patients with a high prevalence of thromboembolic events, ET was associated with reduced ICU mortality without an increased burden of haemorrhagic complications. This study suggests ET strategies are safe and associated with favourable outcomes. Whilst full anticoagulation has been questioned for prophylaxis in these patients, our results suggest that there may nevertheless be a role for enhanced / intermediate levels of prophylaxis. Clinical trials investigating causal relationship between intermediate thromboprophylaxis and clinical outcomes are urgently needed.


Assuntos
Anticoagulantes/efeitos adversos , Tratamento Farmacológico da COVID-19 , Cuidados Críticos/métodos , Pandemias , Tromboembolia Venosa/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , Estado Terminal , Europa (Continente)/epidemiologia , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
12.
Br J Anaesth ; 126(1): 256-264, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32977957

RESUMO

BACKGROUND: Whilst there has been progress in supportive treatment for traumatic brain injury (TBI), specific neuroprotective interventions are lacking. Models of ischaemic heart and brain injury show the therapeutic potential of argon gas, but it is still not known whether inhaled argon (iAr) is protective in TBI. We tested the effects of acute administration of iAr on brain oedema, tissue micro-environmental changes, neurological functions, and structural outcome in a mouse model of TBI. METHODS: Anaesthetised adult C57BL/6J mice were subjected to severe TBI by controlled cortical impact. Ten minutes after TBI, the mice were randomised to 24 h treatments with iAr 70%/O2 30% or air (iCtr). Sensorimotor deficits were evaluated up to 6 weeks post-TBI by three independent tests. Cognitive function was evaluated by Barnes maze test at 4 weeks. MRI was done to examine brain oedema at 3 days and white matter damage at 5 weeks. Microglia/macrophages activation and functional commitment were evaluated at 1 week after TBI by immunohistochemistry. RESULTS: iAr significantly accelerated sensorimotor recovery and improved cognitive deficits 1 month after TBI, with less white matter damage in the ipsilateral fimbria and body of the corpus callosum. Early changes underpinning protection included a reduction of pericontusional vasogenic oedema and of the inflammatory response. iAr significantly reduced microglial activation with increases in ramified cells and the M2-like marker YM1. CONCLUSIONS: iAr accelerates recovery of sensorimotor function and improves cognitive and structural outcome 1 month after severe TBI in adult mice. Early effects include a reduction of brain oedema and neuroinflammation in the contused tissue.


Assuntos
Argônio/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Argônio/administração & dosagem , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Modelos Animais de Doenças , Inflamação/diagnóstico por imagem , Inflamação/tratamento farmacológico , Inflamação/etiologia , Imageamento por Ressonância Magnética , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem , Tempo
13.
BMJ Open ; 10(11): e042093, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33172948

RESUMO

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.


Assuntos
Lesões Encefálicas Traumáticas , Neuroimagem , Biomarcadores , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Humanos , Londres , Estudos Longitudinais , Estudos Prospectivos
14.
Front Neurol ; 8: 450, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28912750

RESUMO

Traumatic brain injury (TBI) is understood as an interplay between the initial injury, subsequent secondary injuries, and a complex host response all of which are highly heterogeneous. An understanding of the underlying biology suggests a number of windows where mechanistically inspired interventions could be targeted. Unfortunately, biologically plausible therapies have to-date failed to translate into clinical practice. While a number of stereotypical pathways are now understood to be involved, current clinical characterization is too crude for it to be possible to characterize the biological phenotype in a truly mechanistically meaningful way. In this review, we examine current and emerging technologies for fuller biochemical characterization by the simultaneous measurement of multiple, diverse biomarkers. We describe how clinically available techniques such as cerebral microdialysis can be leveraged to give mechanistic insights into TBI pathobiology and how multiplex proteomic and metabolomic techniques can give a more complete description of the underlying biology. We also describe spatially resolved label-free multiplex techniques capable of probing structural differences in chemical signatures. Finally, we touch on the bioinformatics challenges that result from the acquisition of such large amounts of chemical data in the search for a more mechanistically complete description of the TBI phenotype.

15.
Front Neurol ; 8: 354, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28790967

RESUMO

Neuroprotection after traumatic brain injury (TBI) is an important goal pursued strenuously in the last 30 years. The acute cerebral injury triggers a cascade of biochemical events that may worsen the integrity, function, and connectivity of the brain cells and decrease the chance of functional recovery. A number of molecules acting against this deleterious cascade have been tested in the experimental setting, often with preliminary encouraging results. Unfortunately, clinical trials using those candidate neuroprotectants molecules have consistently produced disappointing results, highlighting the necessity of improving the research standards. Despite repeated failures in pharmacological neuroprotection, TBI treatment in neurointensive care units has achieved outcome improvement. It is likely that intensive treatment has contributed to this progress offering a different kind of neuroprotection, based on a careful prevention and limitations of intracranial and systemic threats. The natural course of acute brain damage, in fact, is often complicated by additional adverse events, like the development of intracranial hypertension, brain hypoxia, or hypoperfusion. All these events may lead to additional brain damage and worsen outcome. An approach designed for early identification and prompt correction of insults may, therefore, limit brain damage and improve results.

16.
Toxicol Lett ; 255: 43-6, 2016 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-27178268

RESUMO

Lactic acidosis during metformin intoxication is classically mainly attributed to diminished lactate clearance through liver gluconeogenesis. Here we studied 6 healthy, sedated and mechanically ventilated pigs to clarify whether high dose of metformin also increases skeletal muscle lactate production. Each animal had two microdialysis catheters inserted in gluteus muscles, one per side. One catheter was infused with saline (control) while the other one was infused with metformin diluted in saline (1M), both at a rate of 0.3µl/min. Dialysate lactate concentration and lactate-to-pyruvate ratio, a marker of the balance between anaerobic glycolysis and aerobic (mitochondrial) metabolism, were measured every 3h, for 12h. Continuous infusion of metformin caused a progressive rise in dialysate lactate level (p=0.007) and lactate-to-pyruvate ratio (p<0.001) compared to that of saline, as for mitochondrial "poisoning". These findings suggest that skeletal muscle lactate overproduction contributes to the development of metformin-induced lactic acidosis.


Assuntos
Acidose Láctica/induzido quimicamente , Hipoglicemiantes/toxicidade , Ácido Láctico/metabolismo , Metformina/toxicidade , Microdiálise , Músculo Esquelético/efeitos dos fármacos , Acidose Láctica/metabolismo , Animais , Glicólise/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Infusões Parenterais , Metformina/administração & dosagem , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Ácido Pirúvico/metabolismo , Suínos , Fatores de Tempo
17.
J Neurotrauma ; 33(22): 2019-2025, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-26943781

RESUMO

Prognostic models for traumatic brain injury (TBI) are important tools both in clinical practice and research if properly validated, preferably by external validation. Prognostic models also offer the possibility of monitoring performance by comparing predicted outcomes with observed outcomes. In this study, we applied the prognostic models developed by the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) in an Italian multi-center database (Neurolink) with two aims: to compare observed with predicted outcomes and to check for a possible improvement of clinical outcome over the 11 years of patient inclusion in Neurolink. We applied the IMPACT models to patients included in Neurolink between 1997 and 2007. Performance of the models was assessed by determining calibration (with calibration plots) and discrimination (by the area under the receiver operating characteristic curve [AUC]). Logistic regression analysis was used to analyze a possible trend in outcomes over time, adjusted for predicted outcomes. A total of 1401 patients were studied. Patients had a median age of 40 years and 51% had a Glasgow Coma Scale motor score of 5 or 6. The models showed good discrimination, with AUCs of 0.86 (according to the Core Model) and 0.88 (Extended Model), and adequate calibration, with the overall observed risk of unfavorable outcome and mortality being less than predicted. Outcomes significantly improved over time. This study shows that the IMPACT models performed reasonably well in the Neurolink data and can be used for monitoring performance. After adjustment for predicted outcomes with the prognostic models, we observed a substantial improvement of patient outcomes over time in the three Neurolink centers.


Assuntos
Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/mortalidade , Unidades de Terapia Intensiva/tendências , Índices de Gravidade do Trauma , Adulto , Idoso , Bases de Dados Factuais/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
19.
Crit Care ; 19: 420, 2015 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-26627204

RESUMO

INTRODUCTION: Intracranial pressure (ICP) measurement is used to tailor interventions and to assist in formulating the prognosis for traumatic brain injury patients. Accurate data are therefore essential. The aim of this study was to verify the accuracy of ICP monitoring systems on the basis of a literature review. METHODS: A PubMed search was conducted from 1982 to 2014, plus additional references from the selected papers. Accuracy was defined as the degree of correspondence between the pressure read by the catheter and a reference "real" ICP measurement. Studies comparing simultaneous readings from at least two catheters were included. Drift was defined as the loss of accuracy over the monitoring period. Meta-analyses of data from the studies were used to estimate the overall mean difference between simultaneous ICP measurements and their variability. Individual studies were weighted using both a fixed and a random effects model. RESULTS: Of 163 articles screened, 83 compared two intracranial catheters: 64 reported accuracy and 37 drift (some reported both). Of these, 10 and 17, respectively, fulfilled the inclusion criteria for accuracy and zero drift analysis. The combined mean differences between probes were 1.5 mmHg (95 % confidence interval (CI) 0.7-2.3) with the random effects model and 1.6 mmHg (95 % CI 1.3-1.9) with the fixed effects model. The reported mean drift over a long observation period was 0.75 mmHg. No relation was found with the duration of monitoring or differences between various probes. CONCLUSIONS: This study confirms that the average error between ICP measures is clinically negligible. The random effects model, however, indicates that a high percentage of readings may vary over a wide range, with clinical implications both for future comparison studies and for daily care.


Assuntos
Pressão Intracraniana , Monitorização Fisiológica , Lesões Encefálicas/diagnóstico , Lesões Encefálicas/fisiopatologia , Humanos , Monitorização Fisiológica/métodos , Monitorização Fisiológica/normas , Reprodutibilidade dos Testes
20.
Intensive Care Med ; 41(9): 1517-28, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26194024

RESUMO

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.


Assuntos
Microdiálise , Humanos , Microdiálise/métodos , Microdiálise/normas , Guias de Prática Clínica como Assunto
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