Energy failure following traumatic brain injury: Potential mechanisms and impact of normobaric hyperoxia

Cerebral ischaemia is a frequent finding in post mortem studies following traumatic brain injury (TBI), but clinical studies using 15oxygen positron emission tomography (15O PET) suggest that classical ischaemia is uncommon beyond the first 24 hours after injury. Evidence of metabolic failure in the absence of classical ischaemia may represent ongoing neuronal dysfunction and progressive neuronal loss. Any therapeutic intervention that mitigates such metabolic derangements before they result in irreversible neuronal injury may improve tissue fate and improve the functional outcome for patients. Energy failure was spatially defined, characterised, and mapped using 15O and 18Fluoromisinidazole ([18F] FMISO) positron emission tomography. This enabled differentiation of classical ischaemia, diffusion hypoxia, and established infarction, and provided data on the dominant local mechanism at any given time after TBI. My thesis also aimed to examine the utility of diffusion tensor imaging and whole-brain proton MR spectroscopy (WB 1H MRS) as imaging biomarkers to investigate normobaric hyperoxia as a therapeutic option following traumatic brain injury (TBI). Using ([18F] FMISO PET evidence of tissue hypoxia consistent with microvascular ischaemia was found across the injured brain. The impact of normobaric hyperoxia (NBH) was examined in a clinical TBI cohort using diffusion tensor imaging and WB 1H MRS. Some evidence of benefit was found within the perilesional brain, but further studies should examine the value of a longer period of exposure to NBH and whether this has implications for functional outcome.AAGBI, MRC, Wellcome trus

A case of lactic acidosis complicating assessment and management of asthma.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.INTRODUCTION: Lactic acidosis often occurs in severely unwell patients presenting to Accident and Emergency. It is commonly associated with either hypoxia or decreased tissue perfusion secondary due to cardiovascular collapse or sepsis. CASE PRESENTATION: We present a case of severe lactic acidosis in the presence of normal tissue perfusion and oxygenation in a 31-year-old patient with poorly-controlled asthma. Acidosis promptly reversed on discontinuation of inhaled beta-agonists. CONCLUSION: Lactic acidosis secondary to inhaled beta-agonist administration may be a common scenario which can be misinterpreted very easily and can confuse the clinical picture. Further studies will be needed to establish the exact aetiology of this lactic acid production

Perioperative care of a patient with stroke.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Strokes and TIAs, with their high cumulative mortality and morbidity rates, are occurring with increasing frequency in western population 14. As such, it is vital for clinicians to provide optimal medical management in the perioperative period for those patients with this common neurological problem. This review aims to highlight the importance of the perioperative period and the stages of pre-optimization that can be taken by the multi-disciplinary team to aid this 171819. The evidence suggests that there are significant physiological advantages to early invasive monitoring and high dependency care in these complex patients. These cohort of patients are at increased risk of development of respiratory, gastrointestinal, nutritional and electrolyte disturbances so a constant vigil should be exercised in early recognition and treatment

Inter subject variability and reproducibility of diffusion tensor imaging within and between different imaging sessions.

The aim of these studies was to provide reference data on intersubject variability and reproducibility of diffusion tensor imaging. Healthy volunteers underwent imaging on two occasions using the same 3T Siemens Verio magnetic resonance scanner. At each session two identical diffusion tensor sequences were obtained along with standard structural imaging. Fractional anisotropy, apparent diffusion coefficient, axial and radial diffusivity maps were created and regions of interest applied in normalised space. The baseline data from all 26 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were different across the brain. The regional mean (range) coefficient of variation figures for within session reproducibility were 2.1 (0.9-5.5%), 1.2 (0.4-3.9%), 1.2 (0.4-3.8%) and 1.8 (0.4-4.3%) for fractional anisotropy, apparent diffusion coefficient, axial and radial diffusivity, and were lower than between session reproducibility measurements (2.4 (1.1-5.9%), 1.9 (0.7-5.7%), 1.7 (0.7-4.7%) and 2.4 (0.9-5.8%); p<0.001). The calculated overall and within session 95% prediction intervals for zero change were similar. This study provides additional reference data concerning intersubject variability and reproducibility of diffusion tensor imaging conducted within the same imaging session and different imaging sessions. These data can be utilised in interventional studies to quantify change within a single imaging session, or to assess the significance of change in longitudinal studies of brain injury and disease.RCUK, Wellcome, OtherThis is the published version. It was originally published by PLoS in PLoS ONE here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0065941

Comparison of inter subject variability and reproducibility of whole brain proton spectroscopy.

The aim of these studies was to provide reference data on intersubject variability and reproducibility of metabolite ratios for Choline/Creatine (Cho/Cr), N-acetyl aspartate/Choline (NAA/Cho) and N-acetyl aspartate/Creatine (NAA/Cr), and individual signal-intensity normalised metabolite concentrations of NAA, Cho and Cr. Healthy volunteers underwent imaging on two occasions using the same 3T Siemens Verio magnetic resonance scanner. At each session two identical Metabolic Imaging and Data Acquisition Software (MIDAS) sequences were obtained along with standard structural imaging. Metabolite maps were created and regions of interest applied in normalised space. The baseline data from all 32 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were variable across the different brain regions. The within and between session reproducibility measurements were similar for Cho/Cr, NAA/Choline, Cho and Cr (11.8%, 11.4%, 14.3 and 10.6% vs. 11.9%, 11.4%, 13.5% and 10.5% respectively), but for NAA/Creatine and NAA between session reproducibility was lower (9.3% and 9.1% vs. 10.1% and 9.9%; p <0.05). This study provides additional reference data that can be utilised in interventional studies to quantify change within a single imaging session, or to assess the significance of change in longitudinal studies of brain injury and disease.TV Veenith was supported by clinical research training fellowship from the National Institute of Academic Anaesthesia and Raymond Beverly Sackler studentship. VFJN is supported by an NIHR academic clinical fellowship. JPC was supported by Wellcome trust project grant. DKM is supported by an NIHR Senior Investigator Award. This work was supported by a Medical Research Council (UK) Program Grant (Acute brain injury: heterogeneity of mechanisms, therapeutic targets and outcome effects (G9439390 ID 65883)), the UK National Institute of Health Research Biomedical Research Centre at Cambridge, and the Technology Platform funding provided by the UK Department of Health.This article was originally published in PLoS ONE (Veenith TV, Mada M, Carter E, Grossac J, Newcombe V, et al. (2014) Comparison of Inter Subject Variability and Reproducibility of Whole Brain Proton Spectroscopy. PLoS ONE 9(12): e115304. doi:10.1371/journal.pone.0115304

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Management of Malignant Middle Cerebral Artery Infarction

Malignant middle cerebral artery (MCA) infarcts occur in a small subset of patients with ischaemic strokes and lead to high levels of disability and mortality. Over the last 10 years, surgical interventions, in the form of decompressive craniectomies, have become more popular. There is insufficient evidence to support current medical treatments including mannitol, glycerol, steroids, hypertonic saline, and therapeutic hypothermia. Several randomised controlled trials of early decompressive craniectomies in younger patients have shown a significant improvement in functional outcomes and mortality. Questions still need answering regarding the timing of this surgery, long-term survival benefits, and age thresholds. In this review article we will discuss the evidence and uncertainties surrounding the management of malignant MCA infarcts

Pathophysiologic Mechanisms of Cerebral Ischemia and Diffusion Hypoxia in Traumatic Brain Injury.

Importance We have previously combined oxygen-15 positron emission tomography (15O PET) and brain tissue oximetry (BptO2) to demonstrate increased oxygen diffusion gradients in hypoxic regions following traumatic brain injury (TBI). These data are consistent with microvascular ischaemia and are supported by pathological studies showing widespread microvascular collapse, perivascular oedema and microthrombosis associated with selective neuronal loss. 18F-fluoromisonidazole ([18F]FMISO), a PET tracer that undergoes irreversible selective bioreduction within hypoxic cells, could confirm these findings. Objective Combine ([18F]FMISO) and 15O PET to demonstrate the relative burden, distribution and physiological signatures of conventional macrovascular and microvascular ischaemia in early TBI. Design Observational. Setting Neurosciences Critical Care Unit. Participants Ten patients of median age 59 years (range 30–68) within 1-8 days of severe/moderate TBI, and two cohorts of 10 healthy volunteers aged 53 (41–76) and 45 (29–59) years. Exposures Cerebral blood flow (CBF), blood volume (CBV), oxygen metabolism (CMRO2), oxygen extraction fraction (OEF), and brain tissue hypoxia were measured in patients during combined 15O and [18F]FMISO PET imaging. Similar data were obtained from two cohorts of healthy volunteers who underwent either 15O or [18F]FMISO PET. Main Outcome Measures We estimated ischaemic brain volume (IBV) and hypoxic brain volume (HBV), and compared their spatial distribution and physiological signatures. Results Compared to controls, patients showed higher IBV (56(9 – 281) ml vs. 1(0 – 11) ml; p <0.001) and HBV (29 (0 – 106) ml vs. 9(1 – 24) ml; p < 0.05). While both pathophysiological tissue classes were present within injured and normal brain, their spatial distributions were poorly matched. When compared to tissue within the IBV compartment, the HBV compartment showed similar CBF, CBV and CMRO2, but lower OEF (p < 0.001), and more frequently showed CMRO2 values consistent with irreversible injury. Comparison with BptO2 monitoring suggested that the threshold for increased [18F]FMISO trapping is probably < 15 mmHg. Conclusions and relevance Tissue hypoxia following TBI is not confined to regions with structural abnormality, and can occur in the absence of conventional macrovascular ischaemia. This physiological signature is consistent with microvascular ischaemia and is a target for novel neuroprotective strategies.TVV was supported by a clinical research training fellowship from National Institute of Academic Anaesthesia and Raymond Beverly Sackler studentship. TG was supported by a clinical research training fellowship from The Société Française d’Anesthésie et de Réanimation (SFAR). VFJN is supported by a Health Foundation / Academy of Medical Sciences Clinician Scientist Fellowship. DKM is supported by an NIHR Senior Investigator Award. This work was supported by a Wellcome Trust Project Grant (WT093267) and Medical Research Council (UK) Program Grant (Acute brain injury: heterogeneity of mechanisms, therapeutic targets and outcome effects (G9439390 ID 65883)), the UK National Institute of Health Research Biomedical Research Centre at Cambridge, and the Technology Platform funding provided by the UK Department of Health (JPC, DKM, TDF and FIA)