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Programmable variable pressure valves were introduced in the 1980s, providing a non-invasive solution to post-operative alterations of the valve opening pressure to address problems of under or overdrainage. Since their increased use in the treatment of hydrocephalus, there have been case reports of unintentional alterations of the valve opening pressure following exposure to magnetic fields in everyday environments, from televisions to rollercoasters. Here we describe two cases of patients' programmable valves being altered following audiology assessments. We subsequently discuss some of the available research on the safety of these valves in various magnetic field strengths, alongside interim and updated recommendations made by the British Society of Audiologists with regards to testing of children with programmable shunts in place. [ABSTRACT FROM AUTHOR]

Cerebral microdialysis (CMD) catheters allow continuous monitoring of patients' cerebral metabolism in severe traumatic brain injury (TBI). The catheters consist of a terminal semi-permeable membrane that is inserted into the brain's interstitium to allow perfusion fluid to equalize with the surrounding cerebral extracellular environment before being recovered through a central non-porous channel. However, it is unclear how far recovered fluid and suspended metabolites have diffused from within the brain, and therefore what volume or region of brain tissue the analyses of metabolism represent. We assessed diffusion of the small magnetic resonance (MR)-detectible molecule gadobutrol from microdialysis catheters in six subjects (complete data five subjects, incomplete data one subject) who had sustained a severe TBI. Diffusion pattern and distance in cerebral white matter were assessed using T 1 (time for MR spin-lattice relaxation) maps at 1 mm isotropic resolution in a 3 Tesla MR scanner. Gadobutrol at 10 mmol/L diffused from cerebral microdialysis catheters in a uniform spheroidal (ellipsoid of revolution) pattern around the catheters' semipermeable membranes, and across gray matter-white matter boundaries. Evidence of gadobutrol diffusion was found up to a mean of 13.4 ± 0.5 mm (mean ± standard deviation [SD]) from catheters, but with a steep concentration drop off so that ≤50% of maximum concentration was achieved at ∼4 mm, and ≤10% of maximum was found beyond ∼7 mm from the catheters. There was little variation between subjects. The relaxivity of gadobutrol in human cerebral white matter was estimated to be 1.61 ± 0.38 L.mmol -1 sec -1 (mean ± SD); assuming gadobutrol remained extracellular thereby occupying 20% of total tissue volume (interstitium), and concentration equilibrium with perfusion fluid was achieved immediately adjacent to catheters after 24 h of perfusion. No statistically significant change was found in the concentration of the extracellular metabolites glucose, lactate, pyruvate, nor the lactate/pyruvate ratio during gadobutrol perfusion when compared with period of baseline microdialysis perfusion. Cerebral microdialysis allows continuous monitoring of regional cerebral metabolism-the volume of which is now clearer from this study. It also has the potential to deliver small molecule therapies to focal pathologies of the human brain. This study provides a platform for future development of new catheters optimally designed to treat such conditions.

Background: Accurate head circumference (HC) measurement is essential when assessing neonates and infants. Tape measure HC measurements are prone to errors, particularly when performed by parents/guardians, due to individual differences in head shape, hair style and texture, subject cooperation, and examiner techniques, including tape measure placement and tautness. There is, therefore, the need for a more reliable method., Objective: The primary objective of this study was to evaluate the validity, reliability, and consistency of HC app measurement compared to the current standard of practice, serving as a proof-of-concept for use by health care professionals., Methods: We recruited infants attending the neurosurgery clinic, and parents/guardians were approached and consented to participate in the study. Along with the standard head circumference measurement, measurements were taken with the head circumference app (HC app) developed in-house, and we also collected baseline medical history and characteristics. For the statistical analysis, we used RStudio (version 4.1.1). In summary, we analyzed covariance and intraclass correlation coefficient (ICC) to compare the measurement's within-rater and interrater reliability. The F test was used to analyze the variance between measurements and the Bland-Altman agreement, t test, and correlation coefficients were used to compare the tape measurement to the measures taken by the HC app. We also used nonvalidated questionnaires to explore parental or guardians' experiences, assess their views on app utility, and collect feedback., Results: The total number of recruited patients was 37. Comparison between the app measurements and the measurements with a tape measure showed poor reliability (ICC=0.177) and wide within-app variations (ICC=0.341). The agreement between the measurements done by parents/guardians and the tape measurements done by the researcher was good (ICC=0.901). Parental/guardian feedback was overall very positive, with most of the parents/guardians reporting that the app was easy to use (n=31, 84%) and that they are happy to use the app in an unsupervised setting, provided that they are assured of the measurement quality., Conclusions: We developed this project as a proof-of-concept study, and as such, the app has shown great potential to be used both in a clinical setting and by parents/guardians in their own homes., (©Stefan Yordanov, Kalsoom Akhter, Jye Quan Teh, Jawad Naushahi, Ibrahim Jalloh. Originally published in JMIR Formative Research (https://formative.jmir.org), 14.02.2024.)

Traumatic brain injury remains a major cause of mortality and morbidity in children across the world. Current management based on international guidelines focuses on a fixed therapeutic target of less than 20 mm Hg for managing intracranial pressure and 40-50 mm Hg for cerebral perfusion pressure across the pediatric age group. To improve outcome from this complex disease, it is essential to understand the pathophysiological mechanisms responsible for disease evolution by using different monitoring tools. In this narrative review, we discuss the neuromonitoring tools available for use to help guide management of severe traumatic brain injury in children and some of the techniques that can in future help with individualizing treatment targets based on advanced cerebral physiology monitoring., (© 2023. Crown.)

How to optimise glucose metabolism in the traumatised human brain remains unclear, including whether injured brain can metabolise additional glucose when supplied. We studied the effect of microdialysis-delivered 1,2- 13 C 2 glucose at 4 and 8 mmol/L on brain extracellular chemistry using bedside ISCUS flex , and the fate of the 13 C label in the 8 mmol/L group using high-resolution NMR of recovered microdialysates, in 20 patients. Compared with unsupplemented perfusion, 4 mmol/L glucose increased extracellular concentrations of pyruvate (17%, p = 0.04) and lactate (19%, p = 0.01), with a small increase in lactate/pyruvate ratio (5%, p = 0.007). Perfusion with 8 mmol/L glucose did not significantly influence extracellular chemistry measured with ISCUS flex , compared to unsupplemented perfusion. These extracellular chemistry changes appeared influenced by the underlying metabolic states of patients' traumatised brains, and the presence of relative neuroglycopaenia. Despite abundant 13 C glucose supplementation, NMR revealed only 16.7% 13 C enrichment of recovered extracellular lactate; the majority being glycolytic in origin. Furthermore, no 13 C enrichment of TCA cycle-derived extracellular glutamine was detected. These findings indicate that a large proportion of extracellular lactate does not originate from local glucose metabolism, and taken together with our earlier studies, suggest that extracellular lactate is an important transitional step in the brain's production of glutamine., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PJH is a Director of Technicam, the company that manufactures the triple lumen cranial access device used in the study. PJH has no competing non-financial interests with this study. The other authors have no competing financial interests.

Purpose: The aim of the project was to evaluate intra-CSF etoposide administration in a palliative setting for children and young people with relapsed/refractory central nervous system (CNS) tumours, with the primary endpoints being overall survival and progression-free survival time. A safety endpoint was to assess the side effect profile and complications of intra-CSF etoposide., Methods: Thirty-five patients under the age of 30 years (median age: 5.33 years) were enrolled onto the project. The cross-centre study was a service evaluation, with a data collection spreadsheet designed in Nottingham and completed by both Nottingham and Oxford centres. Data was analysed using SPSS, assessing the overall survival and progression-free survival times, as well as the 6-month and 1-year survival rates., Results: The median overall survival and progression-free survival times were 10.97 and 5.91 months, respectively. The 6-month and 1-year overall survival rates were 67% and 48%, and the progression-free survival rates were 50% and 22%. Age at the start of intra-CSF therapy was significantly associated with overall survival (P = 0.046), with the 6 + age group having improved overall survival. Treatment type was significantly associated with overall survival (P = 0.012), with etoposide intra-CSF treatment being associated with improved overall survival. Treatment duration was significantly associated with both overall survival (P < 0.001) and progression-free survival (P < 0.001)., Conclusion: Intra-CSF etoposide treatment has shown to increase both overall and progression-free survival significantly, whilst having few side effects and maintaining a good quality of life for patients, reflecting it as a beneficial therapy in the palliative setting., (© 2023. Crown.)

Cerebral microdialysis may be used in patients with severe brain injury to monitor their cerebral physiology. In this article we provide a concise synopsis with illustrations and original images of catheter types, their structure, and how they function. Where and how catheters are inserted, their identification on imaging modalities (CT and MRI), together with the roles of glucose, lactate/pyruvate ratio, glutamate, glycerol and urea are summarized in acute brain injury. The research applications of microdialysis including pharmacokinetic studies, retromicrodialysis, and its use as a biomarker for efficacy of potential therapies are outlined. Finally, we explore limitations and pitfalls of the technique, as well as potential improvements and future work that is needed to progress and expand the use of this technology., Competing Interests: PH was a director of Technicam (Newton Abbot, UK), the manufacturer of the cranial access device used in Cambridge. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stovell, Helmy, Thelin, Jalloh, Hutchinson and Carpenter.)

Antimicrobial Resistance (AMR) is a growing global health challenge that threatens to undo gains in human and animal health. Prevention and control of AMR requires functional antimicrobial stewardship (AMS) program, which is complex and often difficult to implement in low- and middle-income countries. We aimed to describe the processes of establishing and implementing an AMS program at Connaught Hospital in Sierra Leone. The project involved the setting up of an AMS program, capacity building and performing a global point prevalence survey (GPPS) at Sierra Leone's national referral hospital. Connaught Hospital established a multidisciplinary AMS subcommittee in 2021 to provide AMS services such as awareness campaigns, education and training and review of guidelines. We performed a GPPS on 175 patients, of whom more than half (98, 56.0%) were prescribed an antibiotic: 63 (69.2%) in the surgical wards and 53 (51.2%) in the medical wards. Ceftriaxone (60, 34.3%) and metronidazole (53, 30.3%) were the most common antibiotics prescribed to patients. In conclusion, it is feasible to establish and implement an AMS program in low-income countries, where most hospitalized patients were prescribed an antibiotic.

Introduction: Post-haemorrhagic hydrocephalus is common amongst premature infants and one of the leading indications for paediatric cerebrospinal fluid (CSF) diversion. Permanent CSF diversion is often delayed until the infant is older but there is no clear consensus on the timing for this. The outcomes for permanent shunting in this patient group are poor, with higher rates of failure and infection compared to other aetiologies of hydrocephalus., Methods: We conduct a single-centre retrospective review of infants with post-haemorrhagic hydrocephalus requiring a permanent shunt insertion over a 5-year period. Demographic and clinical data from time of shunt insertion were collected and used to generate generalised linear models (GLMs) to predict shunt success at 12 months after insertion., Results: Twenty-six infants underwent permanent shunting in this period for post-haemorrhagic hydrocephalus, with 10 suffering shunt failure within the first 12 months. The best-performing GLM was able to predict shunt success with a sensitivity of 1 and specificity of 0.90, with head circumference, weight, and corrected age at the time of shunt insertion being the most significantly associated variables for shunt success in this model., Conclusion: Our proof-of-principle study suggests that highly accurate prediction of shunt success for infants with post-haemorrhagic hydrocephalus is possible using routinely available clinical variables. Further work is required to test this model in larger cohorts and validate whether pre-operative use can improve outcomes for this patient group., (© 2022. The Author(s).)

Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral 'mitochondrial dysfunction' (MD). In patients with TBI and MD, we administered disodium 2,3- 13 C 2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13 C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(-12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13 C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.

Background: The current biomarkers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) have limited sensitivity/specificity for diagnosing malignant germ cell tumors (GCTs) and "marker-negative" patients require histological confirmation for diagnosis. However, GCTs at intracranial sites are surgically relatively inaccessible and biopsy carries risks. MicroRNAs from the miR-371~373 and miR-302/367 clusters are over-expressed in all malignant GCTs and, in particular, miR-371a-3p shows elevated serum levels at diagnosis for testicular disease., Methods: Using our robust preamplified qRT-PCR methodology, we quantified miR-371a-3p levels in serum and cerebrospinal fluid (CSF) in a series of 4 representative clinical cases, 3 with intracranial malignant GCT and 1 with Langerhans cell histiocytosis (LCH), compared with appropriate control cases., Results: Serum and/or CSF miR-371a-3p levels distinguished those with intracranial malignant GCTs from LCH and, if known in real time, could have helped clinical management. The benefits would have included (1) the only confirmatory evidence of an intracranial malignant GCT in 1 case, supporting clinical decision making; (2) early detection of intracranial malignant GCT in another, where an elevated CSF miR-371a-3p level preceded the histologically confirmed diagnosis by 2 years; and (3) confirmation of an intracranial malignant GCT relapse with an elevated serum miR-371a-3p level, where serum and CSF AFP and HCG levels were below thresholds for such a diagnosis., Conclusions: This series highlights the potential for microRNA quantification to assist the noninvasive diagnosis, prognostication, and management for patients with intracranial malignant GCTs. Serum and CSF should be collected routinely as part of future studies to facilitate the extension of these findings to larger patient cohorts., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Awake craniotomy with direct cortical stimulation and mapping is the gold standard for resection of lesions near eloquent brain areas, as it can maximize the extent of resection while minimizing the risk of neurological damage. In contrast to the adult population, only small series of awake craniotomies have been reported in children., Aims: The aim of our study is to establish the feasibility of awake craniotomy in the pediatric population., Methods: We performed a retrospective observational study of children undergoing a supratentorial awake craniotomy between January 2009 and April 2019 in a pediatric tertiary care center. Our primary outcome was feasibility of awake craniotomy, defined as the ability to complete the procedure without conversion to general anesthesia. Our secondary outcomes were the incidence of serious intraoperative complications and the mapping completion rate., Results: Thirty procedures were performed in 28 children: 12 females and 16 males. The median age was 14 years (range 7-17). The primary diagnosis was tumor (83.3%), epilepsy (13.3%), and arterio-venous malformation (3.3%). The anesthetic techniques were asleep-awake-asleep (96.7%) and conscious sedation (3.3%), all cases supplemented with scalp block and pin-site infiltration. Awake craniotomy was feasible in 29 cases (96.7%), one patient converted to general anesthesia due to agitation. Serious complications occurred in six patients: agitation (6.7%), seizures (3.3%), increased intracranial pressure (3.3%), respiratory depression (3.3%), and bradycardia (3.3%). All complications were quickly resolved and without major consequences. Cortical mapping was completed in 96.6% cases. New neurological deficits occurred in six patients (20%)-moderate in one case and mild in 5-being all absent at 6 months of follow-up., Conclusion: Awake craniotomy with intraoperative mapping can be successfully performed in children. Adequate patient selection and close cooperation between neurosurgeons, anesthesiologists, neuropsychologists, and neurophysiologists is paramount. Further studies are needed to determine the best anesthetic technique in this population group., (© 2020 John Wiley & Sons Ltd.)

Metabolic dysfunction is a key pathophysiological process in the acute phase of traumatic brain injury (TBI). Although changes in brain glucose metabolism and extracellular lactate/pyruvate ratio are well known, it was hitherto unknown whether these translate to downstream changes in ATP metabolism and intracellular pH. We have performed the first clinical voxel-based in vivo phosphorus magnetic resonance spectroscopy ( 31 P MRS) in 13 acute-phase major TBI patients versus 10 healthy controls (HCs), at 3T, focusing on eight central 2.5 × 2.5 × 2.5 cm 3 voxels per subject. PCr/γATP ratio (a measure of energy status) in TBI patients was significantly higher (median = 1.09) than that of HCs (median = 0.93) (p < 0.0001), due to changes in both PCr and ATP. There was no significant difference in PCr/γATP between TBI patients with favourable and unfavourable outcome. Cerebral intracellular pH of TBI patients was significantly higher (median = 7.04) than that of HCs (median = 7.00) (p = 0.04). Alkalosis was limited to patients with unfavourable outcome (median = 7.07) (p < 0.0001). These changes persisted after excluding voxels with > 5% radiologically visible injury. This is the first clinical demonstration of brain alkalosis and elevated PCr/γATP ratio acutely after major TBI. 31 P MRS has potential for non-invasively assessing brain injury in the absence of structural injury, predicting outcome and monitoring therapy response.

Background: Severe traumatic brain injury (TBI) is a leading cause of mortality in children, but the accurate prediction of outcomes at the point of admission remains very challenging. Admission laboratory results are a promising potential source of prognostic data, but have not been widely explored in paediatric cohorts. Herein, we use machine-learning methods to analyse 14 different serum parameters together and develop a prognostic model to predict 6-month outcomes in children with severe TBI., Methods: A retrospective review of patients admitted to Cambridge University Hospital's Paediatric Intensive Care Unit between 2009 and 2013 with a TBI. The data for 14 admission serum parameters were recorded. Logistic regression and a support vector machine (SVM) were trained with these data against dichotimised outcomes from the recorded 6-month Glasgow Outcome Scale., Results: Ninety-four patients were identified. Admission levels of lactate, H+, and glucose were identified as being the most informative of 6-month outcomes. Four different models were produced. The SVM using just the three most informative parameters was the best able to predict favourable outcomes at 6 months (sensitivity = 80%, specificity = 99%)., Conclusions: Our results demonstrate the potential for highly accurate outcome prediction after severe paediatric TBI using admission laboratory data.

Objective: Polymicrogyria (PMG) is a common malformation of cortical development. Many patients with PMG will have medically refractory epilepsy but the role of epilepsy surgery is unclear. The objective of this study was to assess the efficacy of surgical resection/disconnection in achieving seizure control in pediatric patients with PMG., Methods: A retrospective review of children undergoing epilepsy surgery for PMG between 2002 and 2017 at The Hospital for Sick Children in Toronto, Canada, was performed., Results: A total of 12 children aged 6 months to 17.8 years (median 8.8 years) underwent resective surgery (7 children) or functional hemispherectomy (5 children). Gross total resection or complete disconnection of PMG was carried out in 7 of 12 children. Follow-up duration was between 1 and 9 years (median 2.1 years). Nine children remained seizure-free at last follow-up. Complete resection or disconnection of PMG led to seizure freedom in 6 of 7 patients (86%), whereas subtotal resection produced seizure freedom in 3 of 5 patients (60%)., Significance: We present one of the largest surgical series of pediatric PMG patients. Seizure outcomes were best with complete resection/disconnection of PMG. However, tailored resections based on electroclinical and neuroradiologic data can produce good outcomes and remain an appropriate strategy for patients with extensive PMG., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Metabolic abnormalities occur after traumatic brain injury (TBI). Glucose is conventionally regarded as the major energy substrate, although lactate can also be an energy source. We compared 3- 13 C lactate metabolism in TBI with "normal" control brain and muscle, measuring 13 C-glutamine enrichment to assess tricarboxylic acid (TCA) cycle metabolism. Microdialysis catheters in brains of nine patients with severe TBI, five non-TBI brain surgical patients, and five resting muscle (non-TBI) patients were perfused (24 h in brain, 8 h in muscle) with 8 mmol/L sodium 3- 13 C lactate. Microdialysate analysis employed ISCUS and nuclear magnetic resonance. In TBI, with 3- 13 C lactate perfusion, microdialysate glucose concentration increased nonsignificantly (mean +11.9%, p = 0.463), with significant increases (p = 0.028) for lactate (+174%), pyruvate (+35.8%), and lactate/pyruvate ratio (+101.8%). Microdialysate 13 C-glutamine fractional enrichments (median, interquartile range) were: for C4 5.1 (0-11.1) % in TBI and 5.7 (4.6-6.8) % in control brain, for C3 0 (0-5.0) % in TBI and 0 (0-0) % in control brain, and for C2 2.9 (0-5.7) % in TBI and 1.8 (0-3.4) % in control brain. 13 C-enrichments were not statistically different between TBI and control brain, showing both metabolize 3- 13 C lactate via TCA cycle, in contrast to muscle. Several patients with TBI exhibited 13 C-glutamine enrichment above the non-TBI control range, suggesting lactate oxidative metabolism as a TBI "emergency option."

A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence of hypoxia. We previously showed that succinate can improve brain extracellular chemistry in acute TBI, but it was not clear if this translates to a change in downstream energy metabolism. We studied the effect of microdialysis-delivered succinate on brain energy state (phosphocreatine/ATP ratio (PCr/ATP)) with 31 P MRS at 3T, and tissue NADH/NAD + redox state using microdialysis (L/P ratio) in eight patients with acute major TBI (mean 7 days). Succinate perfusion was associated with increased extracellular pyruvate (+26%, p < 0.0001) and decreased L/P ratio (-13%, p < 0.0001) in patients overall (baseline-vs-supplementation over time), but no clear-cut change in 31 P MRS PCr/ATP existed in our cohort (p > 0.4, supplemented-voxel-vs-contralateral voxel). However, the percentage decrease in L/P ratio for each patient following succinate perfusion correlated significantly with their percentage increase in PCr/ATP ratio (Spearman's rank correlation, r = -0.86, p = 0.024). Our findings support the interpretation that L/P ratio is linked to brain energy state, and that succinate may support brain energy metabolism in select TBI patients suffering from mitochondrial dysfunction.

Depressed skull fractures sustained from golf balls are quite rare. We report such a case in a 16-year old, and demonstrate its appearance in a 3D CT reconstruction.

Following traumatic brain injury, complex cerebral energy perturbations occur. Correlating with unfavourable outcome, high brain extracellular lactate/pyruvate ratio suggests hypoxic metabolism and/or mitochondrial dysfunction. We investigated whether focal administration of succinate, a tricarboxylic acid cycle intermediate interacting directly with the mitochondrial electron transport chain, could improve cerebral metabolism. Microdialysis perfused disodium 2,3- 13 C 2 succinate (12 mmol/L) for 24 h into nine sedated traumatic brain injury patients' brains, with simultaneous microdialysate collection for ISCUS analysis of energy metabolism biomarkers (nine patients) and nuclear magnetic resonance of 13 C-labelled metabolites (six patients). Metabolites 2,3- 13 C 2 malate and 2,3- 13 C 2 glutamine indicated tricarboxylic acid cycle metabolism, and 2,3- 13 C 2 lactate suggested tricarboxylic acid cycle spinout of pyruvate (by malic enzyme or phosphoenolpyruvate carboxykinase and pyruvate kinase), then lactate dehydrogenase-mediated conversion to lactate. Versus baseline, succinate perfusion significantly decreased lactate/pyruvate ratio (p = 0.015), mean difference -12%, due to increased pyruvate concentration (+17%); lactate changed little (-3%); concentrations decreased for glutamate (-43%) (p = 0.018) and glucose (-15%) (p = 0.038). Lower lactate/pyruvate ratio suggests better redox status: cytosolic NADH recycled to NAD + by mitochondrial shuttles (malate-aspartate and/or glycerol 3-phosphate), diminishing lactate dehydrogenase-mediated pyruvate-to-lactate conversion, and lowering glutamate. Glucose decrease suggests improved utilisation. Direct tricarboxylic acid cycle supplementation with 2,3- 13 C 2 succinate improved human traumatic brain injury brain chemistry, indicated by biomarkers and 13 C-labelling patterns in metabolites.

Introduction: Multimodality monitoring is regularly employed in adult traumatic brain injury (TBI) patients where it provides physiologic and therapeutic insight into this heterogeneous condition. Pediatric studies are less frequent., Methods: An analysis of data collected prospectively from 12 pediatric TBI patients admitted to Addenbrooke's Hospital, Pediatric Intensive Care Unit (PICU) between August 2012 and December 2014 was performed. Patients' intracranial pressure (ICP), mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) were monitored continuously using brain monitoring software ICM+®,) Pressure reactivity index (PRx) and 'Optimal CPP' (CPPopt) were calculated. Patient outcome was dichotomized into survivors and non-survivors., Results: At 6 months 8/12 (66%) of the cohort survived the TBI. The median (±IQR) ICP was significantly lower in survivors 13.1±3.2 mm Hg compared to non-survivors 21.6±42.9 mm Hg (p = 0.003). The median time spent with ICP over 20 mm Hg was lower in survivors (9.7+9.8% vs 60.5+67.4% in non-survivors; p = 0.003). Although there was no evidence that CPP was different between survival groups, the time spent with a CPP close (within 10 mm Hg) to the optimal CPP was significantly longer in survivors (90.7±12.6%) compared with non-survivors (70.6±21.8%; p = 0.02). PRx provided significant outcome separation with median PRx in survivors being 0.02±0.19 compared to 0.39±0.62 in non-survivors (p = 0.02)., Conclusion: Our observations provide evidence that multi-modality monitoring may be useful in pediatric TBI with ICP, deviation of CPP from CPPopt, and PRx correlating with patient outcome.

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.

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.

The pathophysiology of traumatic brain (TBI) injury involves changes to glucose uptake into the brain and its subsequent metabolism. We review the methods used to study cerebral glucose metabolism with a focus on those used in clinical TBI studies. Arterio-venous measurements provide a global measure of glucose uptake into the brain. Microdialysis allows the in vivo sampling of brain extracellular fluid and is well suited to the longitudinal assessment of metabolism after TBI in the clinical setting. A recent novel development is the use of microdialysis to deliver glucose and other energy substrates labelled with carbon-13, which allows the metabolism of glucose and other substrates to be tracked. Positron emission tomography and magnetic resonance spectroscopy allow regional differences in metabolism to be assessed. We summarise the data published from these techniques and review their potential uses in the clinical setting.

In traumatic brain injury (TBI) patients, elevation of the brain extracellular lactate concentration and the lactate/pyruvate ratio are well-recognized, and are associated statistically with unfavorable clinical outcome. Brain extracellular lactate was conventionally regarded as a waste product of glucose, when glucose is metabolized via glycolysis (Embden-Meyerhof-Parnas pathway) to pyruvate, followed by conversion to lactate by the action of lactate dehydrogenase, and export of lactate into the extracellular fluid. In TBI, glycolytic lactate is ascribed to hypoxia or mitochondrial dysfunction, although the precise nature of the latter is incompletely understood. Seemingly in contrast to lactate's association with unfavorable outcome is a growing body of evidence that lactate can be beneficial. The idea that the brain can utilize lactate by feeding into the tricarboxylic acid (TCA) cycle of neurons, first published two decades ago, has become known as the astrocyte-neuron lactate shuttle hypothesis. Direct evidence of brain utilization of lactate was first obtained 5 years ago in a cerebral microdialysis study in TBI patients, where administration of (13)C-labeled lactate via the microdialysis catheter and simultaneous collection of the emerging microdialysates, with (13)C NMR analysis, revealed (13)C labeling in glutamine consistent with lactate utilization via the TCA cycle. This suggests that where neurons are too damaged to utilize the lactate produced from glucose by astrocytes, i.e., uncoupling of neuronal and glial metabolism, high extracellular levels of lactate would accumulate, explaining the association between high lactate and poor outcome. Recently, an intravenous exogenous lactate supplementation study in TBI patients revealed evidence for a beneficial effect judged by surrogate endpoints. Here we review the current state of knowledge about glycolysis and lactate in TBI, how it can be measured in patients, and whether it can be modulated to achieve better clinical outcome.

Much progress has been made over the past two decades in the treatment of severe acute brain injury, including traumatic brain injury and subarachnoid hemorrhage, resulting in a higher proportion of patients surviving with better outcomes. This has arisen from a combination of factors. These include improvements in procedures at the scene (pre-hospital) and in the hospital emergency department, advances in neuromonitoring in the intensive care unit, both continuously at the bedside and intermittently in scans, evolution and refinement of protocol-driven therapy for better management of patients, and advances in surgical procedures and rehabilitation. Nevertheless, many patients still experience varying degrees of long-term disabilities post-injury with consequent demands on carers and resources, and there is room for improvement. Biomarkers are a key aspect of neuromonitoring. A broad definition of a biomarker is any observable feature that can be used to inform on the state of the patient, e.g., a molecular species, a feature on a scan, or a monitoring characteristic, e.g., cerebrovascular pressure reactivity index. Biomarkers are usually quantitative measures, which can be utilized in diagnosis and monitoring of response to treatment. They are thus crucial to the development of therapies and may be utilized as surrogate endpoints in Phase II clinical trials. To date, there is no specific drug treatment for acute brain injury, and many seemingly promising agents emerging from pre-clinical animal models have failed in clinical trials. Large Phase III studies of clinical outcomes are costly, consuming time and resources. It is therefore important that adequate Phase II clinical studies with informative surrogate endpoints are performed employing appropriate biomarkers. In this article, we review some of the available systemic, local, and imaging biomarkers and technologies relevant in acute brain injury patients, and highlight gaps in the current state of knowledge.

Background: Increased blood glucose and impaired pressure reactivity (PRx) after traumatic brain injury (TBI) are both known to correlate with unfavorable patient outcome. However, the relationship between these two variables is unknown., Methods: To test the hypothesis that increased blood glucose leads to increased PRx, we retrospectively analyzed data from 86 traumatic brain injured patients admitted to the Neurocritical Care Unit. Data analyzed included arterial glucose concentration, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and end-tidal CO2. PRx was calculated as the moving correlation coefficient between averaged (10 seconds) arterial blood pressure and ICP. One arterial glucose concentration and one time-aligned PRx value were obtained for each patient, during each day until the fifth day after ictus., Results: Mean arterial glucose concentrations during the first 5 days since ictus were positively correlated with mean PRx (Pearson correlation coefficient = 0.25, p = 0.02). The correlation was strongest on the first day after injury (Pearson correlation coefficient = 0.47, p = 0.008)., Conclusion: Our preliminary findings indicate that increased blood glucose may impair cerebrovascular reactivity, potentially contributing to a mechanistic link between increased blood glucose and poorer outcome after TBI.

Increased 'anaerobic' glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-(13)C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. (13)C enrichment for glycolytic 2,3-(13)C2 lactate was the median 5.4% (interquartile range (IQR) 4.6-7.5%) in TBI brain and 4.2% (2.4-4.4%) in 'normal' brain (P<0.01). The ratio of PPP-derived 3-(13)C lactate to glycolytic 2,3-(13)C2 lactate was median 4.9% (3.6-8.2%) in TBI brain and 6.7% (6.3-8.9%) in 'normal' brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 (r=-0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than 'normal' brain. Several TBI patients exhibited PPP-lactate elevation above the 'normal' range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain.