Neuroinflammation and the immune system in hypoxic ischaemic brain injury pathophysiology after cardiac arrest.

Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro-inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia-reperfusion. In particular, interleukin-1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia-reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules.

Clinical targeting of the cerebral oxygen cascade to improve brain oxygenation in patients with hypoxic-ischaemic brain injury after cardiac arrest.

The cerebral oxygen cascade includes three key stages: (a) convective oxygen delivery representing the bulk flow of oxygen to the cerebral vascular bed; (b) diffusion of oxygen from the blood into brain tissue; and (c) cellular utilisation of oxygen for aerobic metabolism. All three stages may become dysfunctional after resuscitation from cardiac arrest and contribute to hypoxic-ischaemic brain injury (HIBI). Improving convective cerebral oxygen delivery by optimising cerebral blood flow has been widely investigated as a strategy to mitigate HIBI. However, clinical trials aimed at optimising convective oxygen delivery have yielded neutral results. Advances in the understanding of HIBI pathophysiology suggest that impairments in the stages of the oxygen cascade pertaining to oxygen diffusion and cellular utilisation of oxygen should also be considered in identifying therapeutic strategies for the clinical management of HIBI patients. Culprit mechanisms for these impairments may include a widening of the diffusion barrier due to peri-vascular oedema and mitochondrial dysfunction. An integrated approach encompassing both intra-parenchymal and non-invasive neuromonitoring techniques may aid in detecting pathophysiologic changes in the oxygen cascade and enable patient-specific management aimed at reducing the severity of HIBI.

Associations between clinical characteristics of cardiac arrest and early CT head findings of hypoxic ischaemic brain injury following out-of-hospital cardiac arrest.

BACKGROUND/OBJECTIVE: Post-cardiac arrest patients are vulnerable to hypoxic-ischaemic brain injury (HIBI), but HIBI may not be identified until computed tomography (CT) scan of the brain is obtained post-resuscitation and stabilization. We aimed to evaluate the association of clinical arrest characteristics with early CT findings of HIBI to identify those at the highest risk for HIBI. METHODS: This is a retrospective analysis of out-of-hospital cardiac arrest (OHCA) patients who underwent whole-body imaging. Head CT reports were analyzed with an emphasis on findings suggestive of HIBI; HIBI was present if any of the following were noted on the neuroradiologist read: global cerebral oedema, sulcal effacement, blurred grey-white junction, and ventricular compression. The primary exposure was duration of cardiac arrest. Secondary exposures included age, cardiac vs noncardiac etiology, and witnessed vs unwitnessed arrest. The primary outcome was CT findings of HIBI. RESULTS: A total of 180 patients (average age 54 years, 32% female, 71% White, 53% witnessed arrest, 32% cardiac etiology of arrest, mean CPR duration of 15 ± 10 minutes) were included in this analysis. CT findings of HIBI were seen in 47 (48.3%) patients. Multivariate logistic regression demonstrated a significant association between CPR duration and HIBI (adjusted OR = 1.1, 95% CI 1.01-1.11, p < 0.01). CONCLUSION: Signs of HIBI are commonly seen on CT head within 6 hours of OHCA, occurring in approximately half of patients, and are associated with CPR duration. Determining risk factors for abnormal CT findings can help clinically identify patients at higher risk for HIBI and target interventions appropriately.

Do changes in SSEP amplitude over time predict the outcome of comatose survivors of cardiac arrest?

AIM: To assess if the amplitude of the N20 wave (N20Amp) of somatosensory evoked potentials (SSEPs) changes between 12-24 h and 72 h from the return of spontaneous circulation (ROSC) after cardiac arrest and if an N20Amp decrease predicts poor neurological outcome (CPC 3-5) at six months. SETTING: Retrospective analysis of the ProNeCA multicentre prognostication study dataset. (NCT03849911). METHODS: In adult comatose cardiac arrest survivors whose SSEPs were recorded at both 12-24 h and 72 h after ROSC, we measured the median N20Amp at each timepoint and the individual change in N20Amp across the two timepoints. We identified their cutoffs for predicting poor outcome with 0% false positive rate (FPR) and compared their sensitivities. RESULTS: We included 236 patients. The median [IQR] N20Amp increased from 1.90 [0.78-4.22] µV to 2.86 [1.52-5.10] µV between 12-24 h and 72 h (p = 0.0019). The N20Amp cutoff for 0% FPR increased from 0.6 µV at 12-24 h to 1.23 µV at 72 h, and its sensitivity increased from 56[48-64]% to 71[63-77]%. Between 12-24 h and 72 h, an N20Amp decrease > 53% predicted poor outcome with 0[0-5]% FPR and 26[19-35]% sensitivity. Its combination with an N20Amp < 1.23 µV at 72 h increased sensitivity by 1% to 72[64-79]%. CONCLUSION: In comatose cardiac arrest survivors, the median N20Amp and its cutoff for predicting poor neurological outcome increase between 12-24 and 72 h after ROSC. An N20Amp decrease greater than 53% between these two timepoints predicts poor outcome with 0% FPR, confirming the unfavourable prognostic signal of a low N20Amp at 72 h.

Neuronal desertification after a direct lightning strike: a case report.

BACKGROUND: Lightning strike is a rare but dramatic cause of injury. Patients admitted to intensive care units (ICUs) with lightning strike frequently have a high mortality and significant long-term morbidity related to a direct brain injury or induced cardiac arrest (CA). CASE PRESENTATION: A 50-year-old Caucasian man was admitted to our hospital after being struck by lightning resulting in immediate CA. Spontaneous circulation was initially restored, and the man was admitted to the ICU, but ultimately died while in hospital due to neurological injury. The computer tomography scan revealed a massive loss of grey-white matter differentiation at the fronto-temporal lobes bilaterally. Somatosensory-evoked potentials demonstrated bilateral absence of the cortical somatosensory N20-potential, and the electroencephalogram recorded minimal cerebral electrical activity. The patient died on day 10 and a post-mortem study revealed a widespread loss of neurons. CONCLUSION: This case study illustrates severe brain injury caused by a direct lighting strike, with the patient presenting an extraordinary microscopic pattern of neuronal desertification.

Neuroprotection by the noble gases argon and xenon as treatments for acquired brain injury: a preclinical systematic review and meta-analysis.

BACKGROUND: The noble gases argon and xenon are potential novel neuroprotective treatments for acquired brain injuries. Xenon has already undergone early-stage clinical trials in the treatment of ischaemic brain injuries, with mixed results. Argon has yet to progress to clinical trials as a treatment for brain injury. Here, we aim to synthesise the results of preclinical studies evaluating argon and xenon as neuroprotective therapies for brain injuries. METHODS: After a systematic review of the MEDLINE and Embase databases, we carried out a pairwise and stratified meta-analysis. Heterogeneity was examined by subgroup analysis, funnel plot asymmetry, and Egger's regression. RESULTS: A total of 32 studies were identified, 14 for argon and 18 for xenon, involving measurements from 1384 animals, including murine, rat, and porcine models. Brain injury models included ischaemic brain injury after cardiac arrest (CA), neurological injury after cardiopulmonary bypass (CPB), traumatic brain injury (TBI), and ischaemic stroke. Both argon and xenon had significant (P<0.001), positive neuroprotective effect sizes. The overall effect size for argon (CA, TBI, stroke) was 18.1% (95% confidence interval [CI], 8.1-28.1%), and for xenon (CA, TBI, stroke) was 34.1% (95% CI, 24.7-43.6%). Including the CPB model, only present for xenon, the xenon effect size (CPB, CA, TBI, stroke) was 27.4% (95% CI, 11.5-43.3%). Xenon, both with and without the CPB model, was significantly (P<0.001) more protective than argon. CONCLUSIONS: These findings provide evidence to support the use of xenon and argon as neuroprotective treatments for acquired brain injuries. Current evidence suggests that xenon is more efficacious than argon overall.

Association of deranged cerebrovascular reactivity with brain injury following cardiac arrest: a post-hoc analysis of the COMACARE trial.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) is one feature of post cardiac arrest encephalopathy. We studied the incidence and features of CVR by near infrared spectroscopy (NIRS) and associations with outcome and biomarkers of brain injury. METHODS: A post-hoc analysis of 120 comatose OHCA patients continuously monitored with NIRS and randomised to low- or high-normal oxygen, carbon dioxide and mean arterial blood pressure (MAP) targets for 48 h. The tissue oximetry index (TOx) generated by the moving correlation coefficient between cerebral tissue oxygenation measured by NIRS and MAP was used as a dynamic index of CVR with TOx > 0 indicating impaired reactivity and TOx > 0.3 used to delineate the lower and upper MAP bounds for disrupted CVR. TOx was analysed in the 0-12, 12-24, 24-48 h time-periods and integrated over 0-48 h. The primary outcome was the association between TOx and six-month functional outcome dichotomised by the cerebral performance category (CPC1-2 good vs. 3-5 poor). Secondary outcomes included associations with MAP bounds for CVR and biomarkers of brain injury. RESULTS: In 108 patients with sufficient data to calculate TOx, 76 patients (70%) had impaired CVR and among these, chronic hypertension was more common (58% vs. 31%, p = 0.002). Integrated TOx for 0-48 h was higher in patients with poor outcome than in patients with good outcome (0.89 95% CI [- 1.17 to 2.94] vs. - 2.71 95% CI [- 4.16 to - 1.26], p = 0.05). Patients with poor outcomes had a decreased upper MAP bound of CVR over time (p = 0.001), including the high-normal oxygen (p = 0.002), carbon dioxide (p = 0.012) and MAP (p = 0.001) groups. The MAP range of maintained CVR was narrower in all time intervals and intervention groups (p < 0.05). NfL concentrations were higher in patients with impaired CVR compared to those with intact CVR (43 IQR [15-650] vs 20 IQR [13-199] pg/ml, p = 0.042). CONCLUSION: Impaired CVR over 48 h was more common in patients with chronic hypertension and associated with poor outcome. Decreased upper MAP bound and a narrower MAP range for maintained CVR were associated with poor outcome and more severe brain injury assessed with NfL. Trial registration ClinicalTrials.gov, NCT02698917 .

Target arterial PO2 according to the underlying pathology: a mini-review of the available data in mechanically ventilated patients.

There is an ongoing discussion whether hyperoxia, i.e. ventilation with high inspiratory O2 concentrations (FIO2), and the consecutive hyperoxaemia, i.e. supraphysiological arterial O2 tensions (PaO2), have a place during the acute management of circulatory shock. This concept is based on experimental evidence that hyperoxaemia may contribute to the compensation of the imbalance between O2 supply and requirements. However, despite still being common practice, its use is limited due to possible oxygen toxicity resulting from the increased formation of reactive oxygen species (ROS) limits, especially under conditions of ischaemia/reperfusion. Several studies have reported that there is a U-shaped relation between PaO2 and mortality/morbidity in ICU patients. Interestingly, these mostly retrospective studies found that the lowest mortality coincided with PaO2 ~ 150 mmHg during the first 24 h of ICU stay, i.e. supraphysiological PaO2 levels. Most of the recent large-scale retrospective analyses studied general ICU populations, but there are major differences according to the underlying pathology studied as well as whether medical or surgical patients are concerned. Therefore, as far as possible from the data reported, we focus on the need of mechanical ventilation as well as the distinction between the absence or presence of circulatory shock. There seems to be no ideal target PaO2 except for avoiding prolonged exposure (> 24 h) to either hypoxaemia (PaO2 < 55-60 mmHg) or supraphysiological (PaO2 > 100 mmHg). Moreover, the need for mechanical ventilation, absence or presence of circulatory shock and/or the aetiology of tissue dysoxia, i.e. whether it is mainly due to impaired macro- and/or microcirculatory O2 transport and/or disturbed cellular O2 utilization, may determine whether any degree of hyperoxaemia causes deleterious side effects.

Selenium-containing protein from selenium-enriched Spirulina platensis antagonizes oxygen glucose deprivation-induced neurotoxicity by inhibiting ROS-mediated oxidative damage through regulating MPTP opening.

CONTEXT: Selenium-containing protein from selenium-enriched Spirulina platensis (Se-SP) (syn. Arthrospira platensis [Microcoleaceae]) showed novel antioxidant activity. However, the protective effect of Se-SP against oxygen glucose deprivation (OGD)-induced neural apoptosis has not been reported yet. OBJECTIVE: To verify whether Se-SP can inhibit OGD-induced neural apoptosis and explore the underlying mechanism. MATERIALS AND METHODS: Primary hippocampal neurons were separated from Sprague-Dawley (SD) rats. 95% N2 + 5% CO2 were employed to establish OGD model. Neurons were treated with 5 and 10 µg/mL Se-SP under OGD condition for 6 h. Neurons without treatment were the control group. Neural viability and apoptosis were detected by MTT, immunofluorescence and western blotting methods. RESULTS: Se-SP significantly improved neuronal viability (from 57.2% to 94.5%) and inhibited apoptosis in OGD-treated primary neurons (from 45.6% to 6.3%), followed by improved neuronal morphology and caspases activation. Se-SP co-treatment also effectively suppressed OGD-induced DNA damage by inhibiting ROS accumulation in neurons (from 225.6% to 106.3%). Additionally, mitochondrial dysfunction was also markedly improved by Se-SP co-treatment via balancing Bcl-2 family expression. Moreover, inhibition of mitochondrial permeability transition pore (MPTP) by CsA (an MPTP inhibitor) dramatically attenuated OGD-induced ROS generation (from 100% to 56.2%), oxidative damage, mitochondrial membrane potential (MPP) loss (from 7.5% to 44.3%), and eventually reversed the neuronal toxicity and apoptosis (from 57.4% to 79.6%). DISCUSSION AND CONCLUSIONS: Se-SP showed enhanced potential to inhibit OGD-induced neurotoxicity and apoptosis by inhibiting ROS-mediated oxidative damage through regulating MPTP opening, indicating that selenium-containing protein showed broad application in the chemoprevention and chemotherapy against human ischaemic brain injury.

The clinical effects of cerebral near-infrared spectroscopy monitoring (NIRS) versus no monitoring: a protocol for a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Multiple clinical conditions are associated with cerebral hypoxia/ischaemia and thereby an increased risk of hypoxic-ischaemic brain injury. Cerebral near-infrared spectroscopy monitoring (NIRS) is a tool to monitor brain oxygenation and perfusion, and the clinical uptake of NIRS has expanded over recent years. Specifically, NIRS is used in the neonatal, paediatric, and adult perioperative and intensive care settings. However, the available literature suggests that clinical benefits and harms of cerebral NIRS monitoring are uncertain. As rates of clinically significant hypoxic-ischaemic brain injuries are typically low, it is difficult for randomised clinical trials to capture a sufficiently large number of events to evaluate the clinical effect of cerebral NIRS monitoring, when focusing on specific clinical settings. The aim of this systematic review will be to evaluate the benefits and harms of clinical care with access to cerebral NIRS monitoring versus clinical care without cerebral NIRS monitoring in children and adults across all clinical settings. METHODS: We will conduct a systematic review with meta-analysis and trial sequential analysis. We will only include randomised clinical trials. The primary outcomes are all-cause mortality, moderate or severe persistent cognitive or neurological deficit, and proportion of participants with one or more serious adverse events. We will search CENTRAL, EMBASE, MEDLINE, and the Science Citation Index Expanded from their inception and onwards. Two reviewers will independently screen all citations, full-text articles, and extract data. The risk of bias will be appraised using the Cochrane risk of bias tool version 2.0. If feasible, we will conduct both random-effects meta-analysis and fixed-effect meta-analysis of outcome data. Additional analysis will be conducted to explore the potential sources of heterogeneity (e.g. risk of bias, clinical setting). DISCUSSION: As we include trials across multiple clinical settings, there is an increased probability of reaching a sufficient information size. However, heterogeneity between the included trials may impair our ability to interpret results to specific clinical settings. In this situation, we may have to depend on subgroup analyses with inherent increased risks of type I and II errors. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020202986 . This systematic review protocol has been submitted for registration in the International Prospective Register of Systematic Reviews (PROSPERO) (http://www.crd.york.ac.uk/prospero) on the 12th of October 2020 and published on the 12th of November 2020 (registration ID CRD42020202986 ).

Neuroprotective Treatment of Postanoxic Encephalopathy: A Review of Clinical Evidence.

Postanoxic encephalopathy is the key determinant of death or disability after successful cardiopulmonary resuscitation. Animal studies have provided proof-of-principle evidence of efficacy of divergent classes of neuroprotective treatments to promote brain recovery. However, apart from targeted temperature management (TTM), neuroprotective treatments are not included in current care of patients with postanoxic encephalopathy after cardiac arrest. We aimed to review the clinical evidence of efficacy of neuroprotective strategies to improve recovery of comatose patients after cardiac arrest and to propose future directions. We performed a systematic search of the literature to identify prospective, comparative clinical trials on interventions to improve neurological outcome of comatose patients after cardiac arrest. We included 53 studies on 21 interventions. None showed unequivocal benefit. TTM at 33 or 36°C and adrenaline (epinephrine) are studied most, followed by xenon, erythropoietin, and calcium antagonists. Lack of efficacy is associated with heterogeneity of patient groups and limited specificity of outcome measures. Ongoing and future trials will benefit from systematic collection of measures of baseline encephalopathy and sufficiently powered predefined subgroup analyses. Outcome measurement should include comprehensive neuropsychological follow-up, to show treatment effects that are not detectable by gross measures of functional recovery. To enhance translation from animal models to patients, studies under experimental conditions should adhere to strict methodological and publication guidelines.

Lack of agreement between optimal mean arterial pressure determination using pressure reactivity index versus cerebral oximetry index in hypoxic ischemic brain injury after cardiac arrest.

INTRODUCTION: Invasive monitoring of cerebral autoregulation using the pressure reactivity index (PRx) allows for the determination of optimal mean arterial pressure (MAPOPT) in hypoxic ischemic brain injury (HIBI) patients following cardiac arrest. However, the utility of non-invasive surrogates to determine MAPOPT has not been addressed. We aimed to determine the agreement between PRx-derived MAPOPT versus MAPOPT determined by the near-infrared spectroscopy (NIRS) based cerebral oximetry index (COx). METHODS: Ten HIBI patients were enrolled. PRx-derived MAPOPT, lower (LLA) and upper limits of autoregulation (ULA) were compared against COx-derived MAPOPT, LLA and ULA. Multimodal neuromonitoring included mean arterial pressure, intracranial pressure, brain tissue oxygenation, jugular venous oxygen saturation, and NIRS-derived regional cerebral oxygen saturation. RESULTS: Repeated measures Bland-Altman plots demonstrated limited agreement between MAPOPT derived from COx and PRx (mean bias: 1.4 mmHg; upper limit of agreement: 25.9 mmHg; lower limit of agreement: -23.0 mmHg). Similarly, there was limited agreement between the absolute values of PRx and COx. Mean bias was 0.26 and the upper and lower limits of agreement were 1.05 and -0.53, respectively. Systematic bias was apparent, whereby at low PRx values COx overestimated PRx and at high PRx values, COx underestimated PRx. COx was limited in its ability to determine impaired autoregulation defined by PRx (receiver operator characteristic area under the curve was 0.488). CONCLUSION: Collectively, we demonstrate that COx-based determination of MAPOPT lacks agreement with MAPOPT derived from PRx. Further research must be done to evaluate the physiologic and clinical efficacy of PRx derived MAPOPT in HIBI.

Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours.

The PI3 K/AKT/mTOR signalling pathway plays an important role in the regulation of signal transduction and biological processes such as cell proliferation, apoptosis, metabolism and angiogenesis. Compared with those of other signalling pathways, the components of the PI3K/AKT/mTOR signalling pathway are complicated. The regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway are important in many human diseases, including ischaemic brain injury, neurodegenerative diseases, and tumours. PI3K/AKT/mTOR signalling pathway inhibitors include single-component and dual inhibitors. Numerous PI3K inhibitors have exhibited good results in preclinical studies, and some have been clinically tested in haematologic malignancies and solid tumours. In this review, we briefly summarize the results of research on the PI3K/AKT/mTOR pathway and discuss the structural composition, activation, communication processes, regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway in the pathogenesis of neurodegenerative diseases and tumours.

Long non-coding RNA Gas5 potentiates the effects of microRNA-21 downregulation in response to ischaemic brain injury.

Brain ischaemia, which can cause severe nerve injury, is a global health challenge. Long non-coding RNA (lncRNA) growth-arrest specific 5 (Gas5) has been documented to exert tumour suppressive effects in several cancers. However, its role in cerebrovascular disease still requires further investigation. Therefore, in this study, we focused on the role of lncRNA regulatory signalling related to lncRNA Gas5 in ischaemic brain injury. Middle cerebral artery occlusion (MCAO) was employed as a model of ischaemic brain injury in rats. The expression of lncRNA Gas5 and microRNA-21 (miR-21) was altered in neurons to elucidate their effects in ischaemic brain injury and to identify the interactions among lncRNA Gas5, miR-21 and Pten. The neuronal survival rate, apoptosis and the expression of phosphatidyl inositol 3-kinase (PI3K)/Akt signalling pathway-related genes were also evaluated in vitro to determine the effects of lncRNA Gas5. In the brains of rats subjected to MCAO, the expression of lncRNA Gas5 and Pten was upregulated, while miR-21 was downregulated. LncRNA Gas5 inhibited miR-21 expression, leading to elevated levels of Pten. In vitro experiments revealed that lncRNA Gas5 depletion and miR-21 elevation resulted in the suppression of neuronal apoptosis, thus promoting neuronal survival via the PI3K/Akt signalling pathway. These findings demonstrate that lncRNA Gas5 increases miR-21 and activates Pten, contributing to the development of ischaemic brain injury, supporting the silencing of lncRNA Gas5 as a possible therapeutic target for the treatment of ischaemic brain injury.

A comparison of non-invasive versus invasive measures of intracranial pressure in hypoxic ischaemic brain injury after cardiac arrest.

AIM: Increased intracranial pressure (ICP) in hypoxic ischaemic brain injury (HIBI) can cause secondary ischaemic brain injury and culminate in brain death. Invasive ICP monitoring is limited by associated risks in HIBI patients. We sought to evaluate the agreement between invasive ICP measurements and non-invasive estimators of ICP (nICP) in HIBI patients. METHODS: Eligible consecutive adult (age>18) cardiac arrest patients with HIBI were included as part of a single centre prospective interventional study. Invasive ICP monitoring and nICP measurements were undertaken using: a) transcranial Doppler ultrasonography (TCD), b) optic nerve sheet diameter ultrasound (ONSD) and c) jugular venous bulb pressure (JVP). Multiple measurements applied in linear mixed-effects models were considered to obtain the correlation coefficient between ICP and nICP as well as their predictive abilities to detect intracranial hypertension (ICP≥20mm Hg). RESULTS: Eleven patients were included (median age of 47 [range 20-71], 8 males and 3 females). There was a linear relationship between ICP and nICP with ONSD (R=0.53 [p<0.0001]), JVP (R=0.38 [p<0.001]) and TCD (R=0.30 [p<0.01]). The ability to predict intracranial hypertension was highest for ONSD and TCD (area under the receiver operating curve (AUC)=0.96 [95% CI: 0.90-1.00] and AUC=0.91 [95% CI: 0.83-1.00], respectively). JVP presented the weakest prediction ability (AUC=0.75 [95% CI: 0.56-0.94]). CONCLUSIONS: ONSD and TCD methods demonstrated agreement with invasively-monitored ICP, suggesting their potential roles in the detection of intracranial hypertension in HIBI after cardiac arrest.

Focal Ischaemic Infarcts Expand Faster in Cerebellar Cortex than Cerebral Cortex in a Mouse Photothrombotic Stroke Model.

It is generally accepted that the cerebellum is particularly vulnerable to ischaemic injury, and this may contribute to the high mortality arising from posterior circulation strokes. However, this has not been systematically examined in an animal model. This study compared the development and resolution of matched photothrombotic microvascular infarcts in the cerebellar and cerebral cortices in adult 129/SvEv mice of both sexes. The photothrombotic lesions were made using tail vein injection of Rose Bengal with a 532 nm laser projected onto a 2 mm diameter aperture over the target region of the brain (with skull thinning). Infarct size was then imaged histologically following 2 h to 30-day survival using serial reconstruction of haematoxylin and eosin stained cryosections. This was complemented with immunohistochemistry for neuron and glial markers. At 2 h post-injury, the cerebellar infarct volume averaged ~ 2.7 times that of the cerebral cortex infarcts. Infarct volume reached maximum in the cerebellum in a quarter of the time (24 h) taken in the cerebral cortex (4 days). Remodelling resolved the infarcts within a month, leaving significantly larger residual injury volume in the cerebellum. The death of neurons in the core lesion at 2 h was confirmed by NeuN and Calbindin immunofluorescence, alongside activation of astrocytes and microglia. The latter persisted in the region within and surrounding the residual infarct at 30 days. This comparison of acute focal ischaemic injuries in cerebellar and cerebral cortices provides direct confirmation of exacerbation of neuropathology and faster kinetics in the cerebellum.

Inhibition of endoplasmic reticulum stress is involved in the neuroprotective effect of aFGF in neonatal hypoxic-ischaemic brain injury.

Acidic fibroblast growth factor (aFGF) has been shown to exert neuroprotective effects in experimental models and human patients. In this study, we investigated whether aFGF intranasal-treatment protected against neonatal hypoxic-ischaemic brain injury and evaluated the role of endoplasmic reticulum stress. The Rice-Vannucci model of neonatal hypoxic-ischaemic brain injury was used in 7-day-old rats, which were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia. Intranasal aFGF or vehicle was administered immediately after hypoxic-ischaemic injury (100 ng/g) and then twice a day for 1 week to evaluate the long-term effects. Here we reported that intranasal-treatment with aFGF significantly reduced hypoxic-ischaemic brain infarct volumes and the protective effects were at least partially via inhibiting endoplasmic reticulum stress. In addition, aFGF exerted long-term neuroprotective effects against brain atrophy and neuron loss at 7-day after injury. Our data indicate that therapeutic strategies targeting endoplasmic reticulum stress may be promising to the treatment of neonatal hypoxic-ischaemic brain injury.

Oxidative stress and endoplasmic reticulum (ER) stress in the development of neonatal hypoxic-ischaemic brain injury.

Birth asphyxia in term neonates affects 1-2/1000 live births and results in the development of hypoxic-ischaemic encephalopathy with devastating life-long consequences. The majority of neuronal cell death occurs with a delay, providing the potential of a treatment window within which to act. Currently, treatment options are limited to therapeutic hypothermia which is not universally successful. To identify new interventions, we need to understand the molecular mechanisms underlying the injury. Here, we provide an overview of the contribution of both oxidative stress and endoplasmic reticulum stress in the development of neonatal brain injury and identify current preclinical therapeutic strategies.

Simultaneous monitoring of potassium, glucose and lactate during spreading depolarization in the injured human brain - Proof of principle of a novel real-time neurochemical analysis system, continuous online microdialysis.

Spreading depolarizations occur spontaneously and frequently in injured human brain. They propagate slowly through injured tissue often cycling around a local area of damage. Tissue recovery after an spreading depolarization requires greatly augmented energy utilisation to normalise ionic gradients from a virtually complete loss of membrane potential. In the injured brain, this is difficult because local blood flow is often low and unreactive. In this study, we use a new variant of microdialysis, continuous on-line microdialysis, to observe the effects of spreading depolarizations on brain metabolism. The neurochemical changes are dynamic and take place on the timescale of the passage of an spreading depolarization past the microdialysis probe. Dialysate potassium levels provide an ionic correlate of cellular depolarization and show a clear transient increase. Dialysate glucose levels reflect a balance between local tissue glucose supply and utilisation. These show a clear transient decrease of variable magnitude and duration. Dialysate lactate levels indicate non-oxidative metabolism of glucose and show a transient increase. Preliminary data suggest that the transient changes recover more slowly after the passage of a sequence of multiple spreading depolarizations giving rise to a decrease in basal dialysate glucose and an increase in basal dialysate potassium and lactate levels.

Relationship Between Cerebral Oxygenation and Metabolism During Rewarming in Newborn Infants After Therapeutic Hypothermia Following Hypoxic-Ischemic Brain Injury.

Therapeutic hypothermia (TH) has become a standard of care following hypoxic ischemic encephalopathy (HIE). After TH, body temperature is brought back to 37 °C over 14 h. Lactate/N-acetylasperatate (Lac/NAA) peak area ratio on proton magnetic resonance spectroscopy ((1)H MRS) is the best available outcome biomarker following HIE. We hypothesized that broadband near infrared spectroscopy (NIRS) measured changes in the oxidation state of cytochrome-c-oxidase concentration (Δ[oxCCO]) and cerebral hemodynamics during rewarming would relate to Lac/NAA. Broadband NIRS and systemic data were collected during rewarming from 14 infants following HIE over a mean period of 12.5 h. (1)H MRS was performed on day 5-9. Heart rate increased by 20/min during rewarming while blood pressure and peripheral oxygen saturation (SpO2) remained stable. The relationship between mitochondrial metabolism and oxygenation (measured as Δ[oxCCO] and Δ[HbD], respectively) was calculated by linear regression analysis. This was reviewed in three groups: Lac/NAA values <0.5, 0.5-1, >1. Mean regression coefficient (r (2)) values in these groups were 0.41 (±0.27), 0.22 (±0.21) and 0.01, respectively. The relationship between mitochondrial metabolism and oxygenation became impaired with rising Lac/NAA. Cardiovascular parameters remained stable during rewarming.