Normobaric hyperoxia does not improve derangements in diffusion tensor imaging found distant from visible contusions following acute traumatic brain injury.

We have previously shown that normobaric hyperoxia may benefit peri-lesional brain and white matter following traumatic brain injury (TBI). This study examined the impact of brief exposure to hyperoxia using diffusion tensor imaging (DTI) to identify axonal injury distant from contusions. Fourteen patients with acute moderate/severe TBI underwent baseline DTI and following one hour of 80% oxygen. Thirty-two controls underwent DTI, with 6 undergoing imaging following graded exposure to oxygen. Visible lesions were excluded and data compared with controls. We used the 99% prediction interval (PI) for zero change from historical control reproducibility measurements to demonstrate significant change following hyperoxia. Following hyperoxia DTI was unchanged in controls. In patients following hyperoxia, mean diffusivity (MD) was unchanged despite baseline values lower than controls (p < 0.05), and fractional anisotropy (FA) was lower within the left uncinate fasciculus, right caudate and occipital regions (p < 0.05). 16% of white and 14% of mixed cortical and grey matter patient regions showed FA decreases greater than the 99% PI for zero change. The mechanistic basis for some findings are unclear, but suggest that a short period of normobaric hyperoxia is not beneficial in this context. Confirmation following a longer period of hyperoxia is required.

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

IMPORTANCE: Combined oxygen 15-labeled positron emission tomography (15O PET) and brain tissue oximetry have demonstrated increased oxygen diffusion gradients in hypoxic regions after traumatic brain injury (TBI). These data are consistent with microvascular ischemia and are supported by pathologic studies showing widespread microvascular collapse, perivascular edema, and microthrombosis associated with selective neuronal loss. Fluorine 18-labeled fluoromisonidazole ([18F]FMISO), a PET tracer that undergoes irreversible selective bioreduction within hypoxic cells, could confirm these findings. OBJECTIVE: To combine [18F]FMISO and 15O PET to demonstrate the relative burden, distribution, and physiologic signatures of conventional macrovascular and microvascular ischemia in early TBI. DESIGN, SETTING, AND PARTICIPANTS: This case-control study included 10 patients who underwent [18F]FMISO and 15O PET within 1 to 8 days of severe or moderate TBI. Two cohorts of 10 healthy volunteers underwent [18F]FMISO or 15O PET. The study was performed at the Wolfson Brain Imaging Centre of Addenbrooke's Hospital. Cerebral blood flow, cerebral blood volume, cerebral oxygen metabolism (CMRO2), oxygen extraction fraction, and brain tissue oximetry were measured in patients during [18F]FMISO and 15O PET imaging. Similar data were obtained from control cohorts. Data were collected from November 23, 2007, to May 22, 2012, and analyzed from December 3, 2012, to January 6, 2016. MAIN OUTCOMES AND MEASURES: Estimated ischemic brain volume (IBV) and hypoxic brain volume (HBV) and a comparison of their spatial distribution and physiologic signatures. RESULTS: The 10 patients with TBI (9 men and 1 woman) had a median age of 59 (range, 30-68) years; the 2 control cohorts (8 men and 2 women each) had median ages of 53 (range, 41-76) and 45 (range, 29-59) years. Compared with controls, patients with TBI had a higher median IBV (56 [range, 9-281] vs 1 [range, 0-11] mL; P < .001) and a higher median HBV (29 [range, 0-106] vs 9 [range, 1-24] mL; P = .02). Although both pathophysiologic tissue classes were present within injured and normal appearing brains, their spatial distributions were poorly matched. When compared with tissue within the IBV compartment, the HBV compartment showed similar median cerebral blood flow (17 [range, 11-40] vs 14 [range, 6-22] mL/100 mL/min), cerebral blood volume (2.4 [range, 1.6- 4.2] vs 3.9 [range, 3.4-4.8] mL/100 mL), and CMRO2 (44 [range, 27-67] vs 71 [range, 34-88] µmol/100 mL/min) but a lower oxygen extraction fraction (38% [range, 29%-50%] vs 89% [range, 75%-100%]; P < .001), and more frequently showed CMRO2 values consistent with irreversible injury. Comparison with brain tissue oximetry monitoring suggested that the threshold for increased [18F]FMISO trapping is probably 15 mm Hg or lower. CONCLUSIONS AND RELEVANCE: Tissue hypoxia after TBI is not confined to regions with structural abnormality and can occur in the absence of conventional macrovascular ischemia. This physiologic signature is consistent with microvascular ischemia and is a target for novel neuroprotective strategies.

Predicting the outcome for individual patients with traumatic brain injury: a case-based review.

BACKGROUND: Traumatic brain injuries result in significant morbidity and mortality. Accurate prediction of prognosis is desirable to inform treatment decisions and counsel family members. Objective To review the currently available prognostic tools for use in traumatic brain injury (TBI), to analyse their value in individual patient management and to appraise ongoing research on prognostic modelling. METHODS AND RESULTS: We present two patients who sustained a TBI in 2011-2012 and evaluate whether prognostic models could accurately predict their outcome. The methodology and validity of current prognostic models are analysed and current research that might contribute to improved individual patient prognostication is evaluated. CONCLUSION: Predicting prognosis in the acute phase after TBI is complex and existing prognostic models are not suitable for use at the individual patient level. Data derived from these models should only be used as an adjunct to clinical judgement and should not be used to set limits for acute care interventions. Information from neuroimaging, physiological monitoring and analysis of biomarkers or genetic polymorphisms may be used in the future to improve accuracy of individual patient prognostication. Clinicians should consider offering full supportive treatment to patients in the early phase after injury whilst the outcome is unclear.

Extracellular N-Acetylaspartate in Human Traumatic Brain Injury.

N-acetylaspartate (NAA) is an amino acid derivative primarily located in the neurons of the adult brain. The function of NAA is incompletely understood. Decrease in brain tissue NAA is presently considered symptomatic and a potential biomarker of acute and chronic neuropathological conditions. The aim of this study was to use microdialysis to investigate the behavior of extracellular NAA (eNAA) levels after traumatic brain injury (TBI). Sampling for this study was performed using cerebral microdialysis catheters (M Dialysis 71) perfused at 0.3 µL/min. Extracellular NAA was measured in microdialysates by high-performance liquid chromatography in 30 patients with severe TBI and for comparison, in radiographically "normal" areas of brain in six non-TBI neurosurgical patients. We established a detailed temporal eNAA profile in eight of the severe TBI patients. Microdialysate concentrations of glucose, lactate, pyruvate, glutamate, and glycerol were measured on an ISCUS clinical microdialysis analyzer. Here, we show that the temporal profile of microdialysate eNAA was characterized by highest levels in the earliest time-points post-injury, followed by a steady decline; beyond 70 h post-injury, average levels were 40% lower than those measured in non-TBI patients. There was a significant inverse correlation between concentrations of eNAA and pyruvate; eNAA showed significant positive correlations with glycerol and the lactate/pyruvate (L/P) ratio measured in microdialysates. The results of this on-going study suggest that changes in eNAA after TBI relate to the release of intracellular components, possibly due to neuronal death or injury, as well as to adverse brain energy metabolism.

Creaming and Parking in Quasi-Marketised Welfare-to-Work Schemes: Designed Out Of or Designed In to the UK Work Programme?

'Creaming' and 'parking' are endemic concerns within quasi-marketised welfare-to-work (WTW) systems internationally, and the UK's flagship Work Programme for the long-term unemployed is something of an international pioneer of WTW delivery, based on outsourcing, payment by results and provider flexibility. In the Work Programme design, providers' incentives to 'cream' and 'park' differently positioned claimants are intended to be mitigated through the existence of nine payment groups (based on claimants' prior benefit type) into which different claimants are allocated and across which job outcome payments for providers differ. Evaluation evidence suggests however that 'creaming' and 'parking' practices remain common. This paper offers original quantitative insights into the extent of claimant variation within these payment groups, which, contrary to the government's intention, seem more likely to design in rather than design out 'creaming' and 'parking'. In response, a statistical approach to differential payment setting is explored and is shown to be a viable and more effective way to design a set of alternative and empirically grounded payment groups, offering greater predictive power and value-for-money than is the case in the current Work Programme design.

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.

Use of diffusion tensor imaging to assess the impact of normobaric hyperoxia within at-risk pericontusional tissue after traumatic brain injury.

Ischemia and metabolic dysfunction remain important causes of neuronal loss after head injury, and we have shown that normobaric hyperoxia may rescue such metabolic compromise. This study examines the impact of hyperoxia within injured brain using diffusion tensor imaging (DTI). Fourteen patients underwent DTI at baseline and after 1 hour of 80% oxygen. Using the apparent diffusion coefficient (ADC) we assessed the impact of hyperoxia within contusions and a 1 cm border zone of normal appearing pericontusion, and within a rim of perilesional reduced ADC consistent with cytotoxic edema and metabolic compromise. Seven healthy volunteers underwent imaging at 21%, 60%, and 100% oxygen. In volunteers there was no ADC change with hyperoxia, and contusion and pericontusion ADC values were higher than volunteers (P<0.01). There was no ADC change after hyperoxia within contusion, but an increase within pericontusion (P<0.05). We identified a rim of perilesional cytotoxic edema in 13 patients, and hyperoxia resulted in an ADC increase towards normal (P=0.02). We demonstrate that hyperoxia may result in benefit within the perilesional rim of cytotoxic edema. Future studies should address whether a longer period of hyperoxia has a favorable impact on the evolution of tissue injury.

Strategies to prevent ventilation-associated pneumonia: the effect of cuff pressure monitoring techniques and tracheal tube type on aspiration of subglottic secretions: an in-vitro study.

BACKGROUND: Ventilation-associated pneumonia (VAP) is the commonest nosocomial infection in intensive care. Implementation of a VAP prevention care bundle is a proven method to reduce its incidence. The UK care bundle recommends maintenance of the tracheal tube cuff pressure at 20 to 30  cmH2O with 4-hourly pressure checks and use of tracheal tubes with subglottic aspiration ports in patients admitted for more than 72  h. OBJECTIVE: To evaluate the effects of tracheal tube type and cuff pressure monitoring technique on leakage of subglottic secretions past the tracheal tube cuff. DESIGN: Bench-top study. SETTING: Laboratory. INTERVENTIONS: A model adult trachea with simulated subglottic secretions was intubated with a tracheal tube with the cuff inflated to 25  cmH2O. Experiments were conducted using a Portex Profile Soft Seal tracheal tube with three cuff pressure monitoring strategies and using a Portex SACETT tracheal tube with intermittent cuff pressure checks. OUTCOME MEASURES: Rate of simulated secretion leakage past the tracheal tube cuff. RESULTS: Mean ±â€ŠSD leakage of fluid past the Profile Soft Seal tracheal tube cuff was 2.25 ±â€Š1.49  ml  min⁻¹ with no monitoring of cuff pressure, 2.98 ±â€Š1.63  ml  min⁻¹ with intermittent cuff pressure monitoring and 3.83 ±â€Š2.17  ml  min⁻¹ with continuous cuff pressure monitoring (P <0.001). Using a SACETT tracheal tube with a subglottic aspiration port and aspirating the simulated secretions prior to intermittent cuff pressure checks reduced the leakage rate to 0.50 ±â€Š0.48  ml  min⁻¹ (P <0.001). CONCLUSION: Subglottic secretions leaked past the tracheal tube cuff with all tube types and cuff pressure monitoring strategies in this model. Significantly higher rates were observed with continuous cuff pressure monitoring and significantly lower rates were observed when using a tracheal tube with a subglottic aspiration port. Further evaluation of medical device performance is needed in order to design more effective VAP prevention strategies.

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.

Imaging in the diagnosis and prognosis of traumatic brain injury.

INTRODUCTION: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Improved understanding of the impact of head injury and the extent and development of neuronal loss and cognitive dysfunction could lead to improved therapy and outcome for patients. AREAS COVERED: This paper reviews the currently available imaging techniques and defines their role in the diagnosis, management and prediction of outcome following traumatic brain injury. These imaging techniques provide delineation of the structural, physiological and functional derangements that result following acute injury, and map their development and association with late functional deficits. Imaging tools also have a role in defining the pathophysiological mechanisms responsible for further neuronal loss following the primary injury. Finally, this paper provides an overview of the role of functional imaging in classifying unresponsive coma and defining functional reorganisation of the brain following injury. EXPERT OPINION: Brain imaging is of key importance in TBI management, enabling efficient and accurate diagnoses to be made, informing management decisions and contributing to prognostication. Developments in imaging techniques promise to improve understanding of the structural and functional derangements, improve management and guide the development and implementation of novel neuroprotective strategies following head injury.