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Abstract The global prevalence rate for congenital hydrocephalus (CH) is approximately one out of every five hundred births with multifaceted predisposing factors at play. Genetic influences stand as a major contributor to CH pathogenesis, and epidemiological evidence suggests their involvement in up to 40% of all cases observed globally. Knowledge about an individual’s genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise genetic etiology has only been pinpointed in fewer than 5% of human instances. More occurrences of CH cases are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci. A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder. This review provides a summary of pertinent genes identified through gene sequencing technologies in humans, in addition to the 4 genes currently associated with CH (two X-linked genes L1CAM and AP1S2, two autosomal recessive MPDZ and CCDC88C). Others predominantly participate in aqueduct abnormalities, ciliary movement, and nervous system development. The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined, focusing mainly on 4 pathways, namely cilia synthesis and movement, ion channels and transportation, Reissner’s fiber (RF) synthesis, cell apoptosis, and neurogenesis. Notably, the proper functioning of motile cilia provides significant impulsion for cerebrospinal fluid (CSF) circulation within the brain ventricles while mutations in cilia-related genes constitute a primary cause underlying this condition. So far, only a limited number of CH-associated genes have been identified in humans. The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field. Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications, such as renal cysts, scoliosis, and cardiomyopathy, as these genes may also play a role in the development of these diseases. Genes discovered in animals present potential targets for new treatments but require further validation through future human studies.

Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Abstract Background Invasive intracranial pressure (ICP) monitoring is a standard practice in severe brain injury cases, where it allows to derive cerebral perfusion pressure (CPP); ICP-tracing can also provide additional information about intracranial dynamics, forecast episodes of intracranial hypertension and set targets for a tailored therapy to prevent secondary brain injury. Nevertheless, controversies about the advantages of an ICP clinical management are still debated. Findings This article reviews recent research on ICP to improve the understanding of the topic and uncover the hidden information in this signal that may be useful in clinical practice. Parameters derived from time-domain as well as frequency domain analysis include compensatory reserve, autoregulation estimation, pulse waveform analysis, and behavior of ICP in time. The possibility to predict the outcome and apply a tailored therapy using a personalised perfusion pressure target is also described. Conclusions ICP is a crucial signal to monitor in severely brain injured patients; a bedside computer can empower standard monitoring giving new metrics that may aid in clinical management, establish a personalized therapy, and help to predict the outcome. Continuous collaboration between engineers and clinicians and application of new technologies to healthcare, is vital to improve the accuracy of current metrics and progress towards better care with individualized dynamic targets.

Introduction: Intracranial pressure (ICP) monitoring is a very commonly performed neurosurgical procedure but there is a wide variation in how it is reported, hindering analysis of it. The current study sought to generate consensus on the reporting of ICP monitoring recording data. Research question: “What should be included in an ICP monitoring report?” Material and methods: The exercise was completed via a modified eDelphi survey. An expert panel discussion was held from which themes were identified and used to produce a code to annotate the transcript of the discussion. Statements were generated for a further two rounds of electronic questionnaires distributed via the REDcap platform. A Likert scale was used to grade agreement with each statement in the survey. A statement was accepted if more than 70% agreement was achieved between respondents. Data was collated using Microsoft Excel and analysed using R. Results: 149 relevant statements were identified from the transcript and categorised into recording parameters, waveform characteristics or reporting. A total of 22 statements were generated for the first round of the survey which was answered by 39 respondents. Following the electronic round of surveys consensus was achieved for all but one statement regarding the acceptability of automating ICP reporting. This was put forward to a second round after which 79% agreement was reached. Discussion and conclusion: The themes and statements from this eDelphi can be used as a framework to allow the standardisation of the reporting of intracranial pressure monitoring data.

Introduction: Pressure reactivity index (PRx) is used for continuous monitoring of cerebrovascular reactivity in traumatic brain injury (TBI). However, PRx has a noisy character. Oscillations in arterial blood pressure (ABP) introduced by cyclic positive end-expiratory pressure adjustment, can make PRx more reliable. However, if oscillations are introduced by the cycling process of an anti-decubitus-mattress the effect on PRx is confounding, as they affect directly also intracranial pressure (ICP). In our routine monitoring in TBI patients we noticed periods of highly regular, slow, spontaneous oscillations in ABP and ICP signals. Research question: We set out to explore the nature of these oscillations and establish if PRx remains reliable during the oscillations. Materials and methods: 10 TBI patients’ recordings with oscillations in ICP and ABP were analysed. We computed PRx, PRx variability (hourly-average of standard-deviation, SD), phase-shift and coherence between ABP and ICP in the slow frequency range. Metrics were compared between oscillation and peri-oscillation periods. Results: During oscillations (frequency 0.006± 0.002Hz), a significantly lower variability of PRx (SD 0.185vs0.242) and higher coherence ABP-ICP (0.618±0.09 vs 0.534 ±0.09) were observed. No external oscillations sources could be identified. 34 out of 48 events showed signs of 'active' transmission associated with negative PRx, indicating a potential positive impact on PRx reliability. Discussion and conclusions: Spontaneous oscillations observed in ABP and ICP signals were found to enhance rather than confound PRx reliability. Further research is warranted to elucidate the nature of these oscillations and develop strategies to leverage them for enhancing PRx reliability in TBI monitoring.

Introduction: Cerebrospinal fluid (CSF) infusion test analysis allows recognizing and appropriately evaluating CSF dynamics in the context of normal pressure hydrocephalus (NPH), which is crucial for effective diagnosis and treatment. However, existing methodology possesses drawbacks that may compromise the precision and interpretation of CSF dynamics parameters. Research question: This study aims to circumvent these constraints by introducing an innovative analysis method grounded in Bayesian inference. Material and methods: A single-centre retrospective cohort study was conducted on 858 patients who underwent a computerized CSF infusion test between 2004 and 2020. We developed a Bayesian framework-based method for parameter estimation and compared the results to the current, gradient descent-based approach. We evaluated the accuracy and reliability of both methods by analysing erroneous prediction rates and curve fitting errors. Results: The Bayesian method surpasses the gradient descent approach, reflected in reduced inaccurate prediction rates and an improved goodness of model fit. On whole cohort level both techniques produced comparable results. However, the Bayesian method holds an added advantage by providing uncertainty intervals for each parameter. Sensitivity analysis revealed significance of the CSF production rate parameter and its interplay with other variables. The resistance to CSF outflow demonstrated excellent robustness. Discussion and conclusion: The proposed Bayesian approach offers a promising solution for improving robustness of CSF dynamics assessment in NPH, based on CSF infusion tests. Additional provision of the uncertainty measure for each diagnostic metric may perhaps help to explain occasional poor diagnostic performance of the test, offering a robust framework for improved understanding and management of NPH.

Introduction: Cerebral autoregulation (CA) dysfunction is a key complication following brain injury. CA assessment using near-infrared spectroscopy (NIRS) offers a promising alternative to the current non-invasive standard, cerebral blood flow velocity (CBFV) measured with transcranial Doppler. Research question: Can autoregulatory slow waves (frequency range 0.005–0.05 Hz) associated with spontaneous and induced changes in ABP in healthy volunteers be detected by parameters measured with the Masimo O3 NIRS device? Methods: ABP, CBFV and Masimo O3 parameters were measured in 10 healthy volunteers at baseline and during ABP oscillations induced by squat/stand manoeuvres. Transmission of slow waves was assessed with power spectral density and coherence analysis in NIRS signals and compared to that of CBFV. Results: At baseline, slow waves were detected with sufficient power that substantially exceeded the signals’ measurement resolution in all parameters except cerebral oxygen saturation. During ABP oscillations in the 0.033 Hz range (induced by squat/stand), the power of slow waves increased in all parameters in a similar pattern, with total (cHb) and oxygenated (O2Hb) haemoglobin concentrations most closely mirroring CBFV (median standardised power [first-third quartile], baseline vs squat/stand: CBFV 0.35 [0.28–0.42] vs 0.50 [0.45–0.62], O2Hb 0.47 [0.33–0.68] vs 0.61 [0.59–0.69]). Coherence with ABP increased for both CBFV and NIRS measures from low at baseline (0.8). Conclusion: Spontaneous fluctuations in ABP can be observed in analysed Masimo O3 metrics to a varying degree. The clinical utility of Masimo O3 signals in CA assessment requires further investigation in brain injury patients.

Introduction: Both intracranial pressure (ICP) and cerebral arterial blood volume (CaBV) have a pulsatile character related to the cardiac cycle. The evolution of the shape of ICP pulses under increasing ICP or decreasing intracranial compliance is well documented. Nevertheless, the exact origin of the alterations in the ICP morphology remains unclear. Research question: Does ICP pulse waveform become similar to non-invasively estimated CaBV pulse during ICP plateau waves. Material and methods: A total of 15 plateau waves recorded in 15 traumatic brain injured patients were analyzed. CaBV pulse waveforms were calculated using global cerebral blood flow model from transcranial Doppler cerebral blood flow velocity (CBFV) signals. The difference index (DI) was used to quantify the similarity between ICP and CaBV waveforms. DI was calculated as the sum of absolute sample-by-sample differences between ICP and CaBV waveforms, representing the area between the pulses. Results: ICP increased (19.4 mm Hg [Q1–Q3: 18.2–23.4 mm Hg] vs. 42.7 mm Hg [Q1–Q3: 36.5–45.1 mm Hg], p

Introduction: PRx can be used as surrogate measure of Cerebral Autoregulation (CA) in traumatic brain injury (TBI) patients. PRx can provide means for individualising cerebral perfusion pressure (CPP) targets, such as CPPopt. However, a recent Delphi consensus of clinicians concluded that consensus could not be reached on the accuracy, reliability, and validation of any current CA assessment method. Research question: We aimed to quantify the short-term uncertainty of PRx time-trends and to relate this to other physiological measurements. Material and methods: Intracranial pressure (ICP), arterial blood pressure (ABP), end-tidal CO2 (EtCO2) high-resolution recordings of 911 TBI patients were processed with ICM + software. Hourly values of metrics that describe the variability within modalities derived from ABP, ICP and EtCO2, were calculated for the first 24h of neuromonitoring. Generalized additive models were used to describe the time trend of the variability in PRx. Linear correlations were studied for describing the relationship between PRx variability and the other physiological modalities. Results: The time profile of variability of PRx decreases over the first 12h and was higher for average PRx ∼0. Increased variability of PRx was not linearly linked with average ABP, ICP, or CPP. For coherence between slow waves of ABP and ICP >0.7, the variability in PRx decreased (R = −0.47, p

Introduction: Secondary insults due to high intracranial pressure (ICP), low cerebral perfusion pressure (CPP) and impaired cerebral pressure reactivity (PRx) predict outcome after severe traumatic brain injury (TBI). Research question: What is the prevalence, co-occurrence and prognostic importance of secondary insults due to deranged ICP, CPP or PRx after TBI. Material and methods: Severe TBI patients requiring ICP monitoring were included. Secondary insults due to ICP, PRx, and CPP were defined as having at least 1 h with a mean value above (or below for CPP) a respective threshold (ICP 20, CPP 60, and PRx 0.25). Percentage time with isolated or co-occurring insults was calculated (impaired ICP only, CPP only, PRx only, ICP and PRx, ICP and CPP, CPP and PRx, ICP CPP and PRx). Prognostic importance for mortality was assessed using a logistic regression model. Results: 822 patients were included of which 76% had elevated ICP, 92% had disturbed pressure reactivity and 55% had low CPP for at least an hour. Out of the total 115,459 h, 46,111 (40%) were spent with at least one variable within the defined secondary injury range. Odds ratios for mortality were greater for combined (impaired ICP, CPP and PRx OR 1.17 95%CI 1.09 to 1.28) than isolated insults (impaired ICP only OR 1.01 95%CI 1.00–1.02, impaired CPP only 1.00 95%CI 0.95–1.05). Discussion and conclusion: ICP and autoregulation insults are common after TBI and often occur independently. Concurrent ICP, CPP and PRx insults portend worse prognosis than when a single variable is deranged.

Introduction: Electrical-equivalence mathematical models that integrate vascular and cerebrospinal fluid (CSF) compartments perform well in simulations of dynamic cerebrovascular variations and their transient effects on intracranial pressure (ICP). However, ICP changes due to sustained vascular diameter changes have not been comprehensively examined. We hypothesise that changes in cerebrovascular resistance (CVR) alter the resistance of the bulk flow of interstitial fluid (ISF). Research question: We hypothesise that changes in CVR alter the resistance of the bulk flow of ISF, thus allowing simulations of ICP in response to sustained vascular diameter changes. Material and methods: A lumped parameter model with vascular and CSF compartments was constructed and converted into an electrical analogue. The flow and pressure responses to transient hyperaemic response test (THRT) and CSF infusion test (IT) were observed. Arterial blood pressure (ABP) was manipulated to simulate ICP plateau waves. The experiments were repeated with a modified model that included the ISF compartment. Results: Simulations of the THRT produced identical cerebral blood flow (CBF) responses. ICP generated by the new model reacted in a similar manner as the original model during ITs. Plateau pressure reached during ITs was however higher in the ISF model. Only the latter was successful in simulating the onset of ICP plateau waves in response to selective blood pressure manipulations. Discussion and conclusion: Our simulations highlighted the importance of including the ISF compartment, which provides mechanism explaining sustained haemodynamic influences on ICP. Consideration of such interactions enables accurate simulations of the cerebrovascular effects on ICP.

Introduction: A fixed CSF pressure (CSFp) of 25 cmH2O (18 mmHg) has been utilised to date to define and classify pseudotumour cerebri syndrome (PTCS). Furthermore, ICP monitoring, and CSF infusion tests have not been frequently performed in this group of patients. Research question: We aimed to report typical, unusual and unstable patterns of ICP in patients with PTCS. Material and methods: We reviewed the recordings of CSF infusion tests and overnight ICP monitoring of patients with suspected or confirmed IIH between January 2003–December 2020.We excluded all patients with a shunt in situ and selected recordings that represented unstable patterns of ICP changes in PTCS. Results: 463 CSF infusion tests and 26 ICP monitorings of PTCS patients had been performed in this timeframe. We divided results of observed pattern into two group: those with known venous sinus measurements (Group A) and those without (Group B). Observed recordings formed a total of 5 and 4 different patterns respectively, based on the behaviour of ICP and slow waves at rest, overnight, and during infusion as well as in relationship to the clinical presentation of each patient. Discussion and conclusion: Accurate monitoring of ICP in PTCS is quintessential. Full understanding of each element of its pathophysiology and their interaction would be essential and include quantification of the CSF pressure not only as a number, but also with consideration of its dynamic contents. Cerebral venous pressure measurements and/or monitoring may be useful. Consideration of the presence or absence of papilloedema in the context of disturbed CSF dynamics could reveal further diagnostic and therapeutic insights.

Introduction: Continuous monitoring of the pressure reactivity index (PRx) provides an estimation of dynamic cerebral autoregulation (CA) at the bedside in traumatic brain injury (TBI) patients. Visualising the time-trend of PRx with a risk bar chart in ICM + software at the bedside allows for better real-time interpretability of the autoregulation status. When PRx>0.3 is sustained for long periods, typically of at least half an hour, the bar shows a pattern called “red solid line” (RSL). RSL was previously described to precede refractory intracranial hypertension and brain death. Research question: We aimed to describe pathophysiological changes in measured signals/parameters during RSL. Material and methods: Observation of time-trends of PRx, intracranial pressure, cerebral perfusion pressure, brain oxygenation and compensatory reserve of TBI patients with RSL. Results: Three pathophysiological patterns were identified: RSL precedes intracranial hypertension, RSL is preceded by intracranial hypertension, or RSL is preceded by brain hypoperfusion. In all cases, RSL was followed by death and the RSL onset was between 1 h and 1 day before the terminal event. Discussion and conclusion: RSL precedes death in intensive care and could represent a marker for terminal clinical deterioration in TBI patients. These findings warrant further investigations in larger cohorts to characterise pathophysiological mechanisms underlying the RSL pattern and whether RSL has a significant relationship with outcome after TBI.

Abstract Background A previous retrospective single-centre study suggested that the percentage of time spent with cerebral perfusion pressure (CPP) below the individual lower limit of reactivity (LLR) is associated with mortality in traumatic brain injury (TBI) patients. We aim to validate this in a large multicentre cohort. Methods Recordings from 171 TBI patients from the high-resolution cohort of the CENTER-TBI study were processed with ICM+ software. We derived LLR as a time trend of CPP at a level for which the pressure reactivity index (PRx) indicates impaired cerebrovascular reactivity with low CPP. The relationship with mortality was assessed with Mann-U test (first 7-day period), Kruskal–Wallis (daily analysis for 7 days), univariate and multivariate logistic regression models. AUCs (CI 95%) were calculated and compared using DeLong’s test. Results Average LLR over the first 7 days was above 60 mmHg in 48% of patients. %time with CPP

Abstract Introduction Lung protective ventilation (LPV) comprising low tidal volume (VT) and high positive end-expiratory pressure (PEEP) may compromise cerebral perfusion in acute brain injury (ABI). In patients with ABI, we investigated whether LPV is associated with increased intracranial pressure (ICP) and/or deranged cerebral autoregulation (CA), brain compensatory reserve and oxygenation. Methods In a prospective, crossover study, 30 intubated ABI patients with normal ICP and no lung injury were randomly assigned to receive low VT [6 ml/kg/predicted (pbw)]/at either low (5 cmH2O) or high PEEP (12 cmH2O). Between each intervention, baseline ventilation (VT 9 ml/kg/pbw and PEEP 5 cmH2O) were resumed. The safety limit for interruption of the intervention was ICP above 22 mmHg for more than 5 min. Airway and transpulmonary pressures were continuously monitored to assess respiratory mechanics. We recorded ICP by using external ventricular drainage or a parenchymal probe. CA and brain compensatory reserve were derived from ICP waveform analysis. Results We included 27 patients (intracerebral haemorrhage, traumatic brain injury, subarachnoid haemorrhage), of whom 6 reached the safety limit, which required interruption of at least one intervention. For those without intervention interruption, the ICP change from baseline to “low VT/low PEEP” and “low VT/high PEEP” were 2.2 mmHg and 2.3 mmHg, respectively, and considered clinically non-relevant. None of the interventions affected CA or oxygenation significantly. Interrupted events were associated with high baseline ICP (p

Summary: Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014–2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12–26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p

Background: Cerebral autoregulation is the mechanism that allows to maintain the stability of cerebral blood flow despite changes in cerebral perfusion pressure. Maneuvers which increase intrathoracic pressure, such as the application of positive end-expiratory pressure (PEEP), have been always challenged in brain injured patients for the risk of increasing intracranial pressure (ICP) and altering autoregulation. The primary aim of this study is to assess the effect of PEEP increase (from 5 to 15 cmH2O) on cerebral autoregulation. Secondary aims include the effect of PEEP increase on ICP and cerebral oxygenation.Material and Methods: Prospective, observational study including adult mechanically ventilated patients with acute brain injury requiring invasive ICP monitoring and undergoing multimodal neuromonitoring including ICP, cerebral perfusion pressure (CPP) and cerebral oxygenation parameters obtained with near-infrared spectroscopy (NIRS), and an index which expresses cerebral autoregulation (PRx). Additionally, values of arterial blood gases were analyzed at PEEP of 5 and 15 cmH2O. Results are expressed as median (interquartile range).Results: Twenty-five patients were included in this study. The median age was 65 years (46–73). PEEP increase from 5 to 15 cmH2O did not lead to worsened autoregulation (PRx, from 0.17 (−0.003–0.28) to 0.18 (0.01-0.24), p = 0.83). Although ICP and CPP changed significantly (ICP: 11.11 (6.73–15.63) to 13.43 (6.8–16.87) mm Hg, p = 0.003, and CPP: 72.94 (59.19–84) to 66.22 (58.91–78.41) mm Hg, p = 0.004), these parameters did not reach clinically relevant levels. No significant changes in relevant cerebral oxygenation parameters were observed.Conclusion: Slow and gradual increases of PEEP did not alter cerebral autoregulation, ICP, CPP and cerebral oxygenation to levels triggering clinical interventions in acute brain injury patients.

Take home message In this review article, we present current and novel theories of CSF circulation and pathophysiology of hydrocephalus, along with results from infusion studies for evaluating CSF dynamics at the bedside.

Introduction Studying cerebral autoregulation, particularly PRx (Pressure Reactivity Index), is commonly employed in adult traumatic brain injury (TBI) and gives real-time information about intracranial pathophysiology, which can help in patient management. Experience in paediatric TBI (PTBI) is limited to single-centre studies despite disproportionately higher incidence of morbidity and mortality in PTBI than in adult TBI.Project We describe the protocol to study cerebral autoregulation using PRx in PTBI. The project called Studying Trends of Auto-Regulation in Severe Head Injury in Paediatrics is a multicentre prospective ethics approved research database study from 10 centres across the UK. Recruitment started in July 2018 with financial support from local/national charities (Action Medical Research for Children, UK).Methods and analysis The first phase of the project is powered to detect optimal thresholds of PRx associated with favourable outcome in PTBI by recruiting 135 patients (initial target of 3 years which has changed to 5 years due to delays related to COVID-19 pandemic) from 10 centres in the UK with outcome follow-up to 1-year postictus. The secondary objectives are to characterise patterns of optimal cerebral perfusion pressure in PTBI and compare the fluctuations in these measured parameters with outcome. The goal is to create a comprehensive research database of a basic set of high-resolution (full waveforms resolution) neuromonitoring data in PTBI for scientific use.Ethics and dissemination Favourable ethical approval has been provided by Health Research Authority, Southwest-Central Bristol Research Ethics Committee (Ref: 18/SW/0053). Results will be disseminated via publications in peer-reviewed medical journals and presentations at national and international conferences.Trial registration number NCT05688462.

Introduction: Potential detrimental effects of hyperoxemia on outcomes have been reported in critically ill patients. Little evidence exists on the effects of hyperoxygenation and hyperoxemia on cerebral physiology. The primary aim of this study is to assess the effect of hyperoxygenation and hyperoxemia on cerebral autoregulation in acute brain injured patients. We further evaluated potential links between hyperoxemia, cerebral oxygenation and intracranial pressure (ICP).Methods: This is a single center, observational, prospective study. Acute brain injured patients [traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracranial hemorrhage (ICH)] undergoing multimodal brain monitoring through a software platform (ICM+) were included. Multimodal monitoring consisted of invasive ICP, arterial blood pressure (ABP) and near infrared spectrometry (NIRS). Derived parameters of ICP and ABP monitoring included the pressure reactivity index (PRx) to assess cerebral autoregulation. ICP, PRx, and NIRS-derived parameters (cerebral regional saturation of oxygen, changes in concentration of regional oxy- and deoxy-hemoglobin), were evaluated at baseline and after 10 min of hyperoxygenation with a fraction of inspired oxygen (FiO2) of 100% using repeated measures t-test or paired Wilcoxon signed-rank test. Continuous variables are reported as median (interquartile range).Results: Twenty-five patients were included. The median age was 64.7 years (45.9–73.2), and 60% were male. Thirteen patients (52%) were admitted for TBI, 7 (28%) for SAH, and 5 (20%) patients for ICH. The median value of systemic oxygenation (partial pressure of oxygen-PaO2) significantly increased after FiO2 test, from 97 (90–101) mm Hg to 197 (189–202) mm Hg, p < 0.0001. After FiO2 test, no changes were observed in PRx values (from 0.21 (0.10–0.43) to 0.22 (0.15–0.36), p = 0.68), nor in ICP values (from 13.42 (9.12–17.34) mm Hg to 13.34 (8.85–17.56) mm Hg, p = 0.90). All NIRS-derived parameters reacted positively to hyperoxygenation as expected. Changes in systemic oxygenation and the arterial component of cerebral oxygenation were significantly correlated (respectively ΔPaO2 and ΔO2Hbi; r = 0.49 (95% CI = 0.17–0.80).Conclusion: Short-term hyperoxygenation does not seem to critically affect cerebral autoregulation.

The shape of the pulse waveforms of intracranial pressure (ICP) and cerebral blood flow velocity (CBFV) typically contains three characteristic peaks. It was reported that alterations in cerebral hemodynamics may influence the shape of the pulse waveforms by changing peaks’ configuration. However, the changes in peak appearance time (PAT) in ICP and CBFV pulses are only described superficially. We analyzed retrospectively ICP and CBFV signals recorded in traumatic brain injury patients during decrease in ICP induced by hypocapnia (n = 11) and rise in ICP during episodes of ICP plateau waves (n = 8). All three peaks were manually annotated in over 48 thousand individual pulses. The changes in PAT were compared between periods of vasoconstriction (expected during hypocapnia) and vasodilation (expected during ICP plateau waves) and their corresponding baselines. Correlation coefficient (rS) analysis between mean ICP and mean PATs was performed in each individual recording. Vasodilation prolonged PAT of the first peaks of ICP and CBFV pulses and the third peak of CBFV pulse. It also accelerated PAT of the third peak of ICP pulse. In contrast, vasoconstriction shortened appearance time of the first peaks of ICP and CBFV pulses and the second peak of ICP pulses. Analysis of individual recordings demonstrated positive association between changes in PAT of all three peaks in the CBFV pulse and mean ICP (rS range: 0.32–0.79 for significant correlations). Further study is needed to test whether PAT of the CBFV pulse may serve as an indicator of changes in ICP–this may open a perspective for non-invasive monitoring of alterations in mean ICP.

Cerebral multimodality monitoring (MMM) is, even with a general lack of Class I evidence, increasingly recognized as a tool to support clinical decision-making in the neuroscience intensive care unit (NICU). However, literature and guidelines have focused on unimodal signals in a specific form of acute brain injury. Integrating unimodal signals in multiple signal monitoring is the next step for clinical studies and patient care. As such, we aimed to investigate the recent application of MMM in studies of adult patients with traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), acute ischemic stroke (AIS), and hypoxic ischemic brain injury following cardiac arrest (HIBI). We identified continuous or daily updated monitoring modalities and summarized the monitoring setting, study setting, and clinical characteristics. In addition, we discussed clinical outcome in intervention studies. We identified 112 MMM studies, including 11 modalities, over the last 7 years (2015–2022). Fifty-eight studies (52%) applied only two modalities. Most frequently combined were ICP monitoring (92 studies (82%)) together with PbtO2 (63 studies (56%). Most studies included patients with TBI (59 studies) or SAH (53 studies). The enrollment period of 34 studies (30%) took more than 5 years, whereas the median sample size was only 36 patients (q1- q3, 20–74). We classified studies as either observational (68 studies) or interventional (44 studies). The interventions were subclassified as systemic (24 studies), cerebral (10 studies), and interventions guided by MMM (11 studies). We identified 20 different systemic or cerebral interventions. Nine (9/11, 82%) of the MMM-guided studies included clinical outcome as an endpoint. In 78% (7/9) of these MMM-guided intervention studies, a significant improvement in outcome was demonstrated in favor of interventions guided by MMM. Clinical outcome may be improved with interventions guided by MMM. This strengthens the belief in this application, but further interdisciplinary collaborations are needed to overcome the heterogeneity, as illustrated in the present review. Future research should focus on increasing sample sizes, improved data collection, refining definitions of secondary injuries, and standardized interventions. Only then can we proceed with complex outcome studies with MMM-guided treatment.

ObjectiveSpine injury is highly prevalent in patients with poly-trauma, but data on the co-occurrence of spine trauma in patients with traumatic brain injury (TBI) are scarce. In this study, we used the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) database to assess the prevalence, characteristics, and outcomes of patients with TBI and a concurrent traumatic spinal injury (TSI).MethodsData from the European multi-center CENTER-TBI study were analyzed. Adult patients with TBI (≥18 years) presenting with a concomitant, isolated TSI of at least serious severity (Abbreviated Injury Scale; AIS ≥3) were included. For outcome analysis, comparison groups of TBI patients with TSI and systemic injuries (non-isolated TSI) and without TSI were created using propensity score matching. Rates of mortality, unfavorable outcomes (Glasgow Outcome Scale Extended; GOSe < 5), and full recovery (GOSe 7–8) of all patients and separately for patients with only mild TBI (mTBI) were compared between groups at 6-month follow-up.ResultsA total of 164 (4%) of the 4,254 CENTER-TBI core study patients suffered from a concomitant isolated TSI. The median age was 53 [interquartile range (IQR): 37–66] years and 71% of patients were men. mTBI was documented in 62% of cases, followed by severe TBI (26%), and spine injuries were mostly cervical (63%) or thoracic (31%). Surgical spine stabilization was performed in 19% of cases and 57% of patients were admitted to the ICU. Mortality at 6 months was 11% and only 36% of patients regained full recovery. There were no significant differences in the 6-month rates of mortality, unfavorable outcomes, or full recovery between TBI patients with and without concomitant isolated TSI. However, concomitant non-isolated TSI was associated with an unfavorable outcome and a higher mortality. In patients with mTBI, a negative association with full recovery could be observed for both concomitant isolated and non-isolated TSI.ConclusionRates of mortality, unfavorable outcomes, and full recovery in TBI patients with and without concomitant, isolated TSIs were comparable after 6 months. However, in patients with mTBI, concomitant TSI was a negative predictor for a full recovery. These findings might indicate that patients with moderate to severe TBI do not necessarily exhibit worse outcomes when having a concomitant TSI, whereas patients with mTBI might be more affected.

Background:The aim of this study was to create a simplistic taxonomy to improve transparency and consistency in, and reduce complexity of, interpreting diffusion tensor imaging (DTI) profiles in white matter disruption. Using a novel strategy of a periodic table of DTI elements, we examined if DTI profiles could demonstrate neural properties of disruption sufficient to characterize white matter changes specific for hydrocephalus vs. non-hydrocephalus, and to distinguish between cohorts of neural injury by their differing potential for reversibility.MethodsDTI datasets from three clinical cohorts representing pathological milestones from reversible to irreversible brain injury were compared to those of healthy controls at baseline, over time and with interventions. The final dataset comprised patients vs. controls in the following groupings: mild traumatic brain injury (mTBI), n = 24 vs. 27, normal pressure hydrocephalus (NPH), n = 16 vs. 9 and Alzheimer's disease (AD), n = 27 vs. 47. We generated DTI profiles from fractional anisotropy (FA) and mean, axial and radial diffusivity measures (MD, L1 and L2 and 3 respectively), and constructed an algorithm to map changes consistently to a periodic table of elements, which fully described their diffusivity and neural properties.ResultsMapping tissue signatures to a periodic table of DTI elements rapidly characterized cohorts by their differing patterns of injury. At baseline, patients with mTBI displayed the most preserved tracts. In NPH, the magnitude of changes was dependent on “familial” DTI neuroanatomy, i.e., potential for neural distortion from risk of ventriculomegaly. With time, patients with Alzheimer's disease were significantly different to controls across multiple measures. By contrast, patients with mTBI showed both loss of integrity and pathophysiological processes of neural repair. In NPH, some patterns of injury, such as “stretch/compression” and “compression” were more reversible following intervention than others; these neural profile properties suggested “microstructural resilience” to injury.ConclusionUsing the novel strategy of a periodic table of DTI elements, our study has demonstrated it is possible to distinguish between different cohorts along the spectrum of brain injury by describing neural profile properties of white matter disruption. Further work to contribute datasets of disease toward this proposed taxonomic framework would enhance the translatability of DTI profiles to the clinical-research interface.

ObjectiveNormal pressure hydrocephalus (NPH) is a neurological condition characterized by a clinical triad of gait disturbance, cognitive impairment, and urinary incontinence in conjunction with ventriculomegaly. Other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and vascular dementia share some overlapping clinical features. However, there is evidence that patients with comorbid NPH and Alzheimer's or Parkinson's disease may still exhibit good clinical response after CSF diversion. This study aims to evaluate clinical responses after ventriculo-peritoneal shunt (VPS) in a cohort of patients with coexisting NPH and neurodegenerative disease.MethodsThe study has two components; (i) a pilot study was performed that specifically focused upon patients with Complex NPH and following the inclusion of the Complex NPH subtype into consideration for the clinical NPH programme, (ii) a retrospective snapshot study was performed to confirm and characterize differences between Classic and Complex NPH patients being seen consecutively over the course of 1 year within a working subspecialist NPH clinic. We studied the characteristics of patients with Complex NPH, utilizing clinical risk stratification and multimodal biomarkers.ResultsThere was no significant difference between responders and non-responders to CSF diversion on comorbidity scales. After VPS insertion, significantly more Classic NPH patients had improved cognition compared to Complex NPH patients (p = 0.005). Improvement in gait and urinary symptoms did not differ between the groups. 26% of the Classic NPH group showed global improvement of the triad, and 42% improved in two domains. Although only 8% showed global improvement of the triad, all Complex NPH patients improved in gait.ConclusionsOur study has demonstrated that the presence of neurodegenerative disorders co-existing with NPH should not be the sole barrier to the consideration of high-volume tap test or lumbar drainage via a specialist NPH programme. Further characterization of distinct cohorts of NPH with differing degrees of CSF responsiveness due to overlay from neurodegenerative or comorbidity risk burden may aid toward more precise prognostication and treatment strategies. We propose a simplistic conceptual framework to describe NPH by its Classic vs. Complex subtypes to promote the clinical paradigm shift toward subspecialist geriatric neurosurgery by addressing needs for rapid screening tools at the clinical-research interface.

Abstract Background Although widely used in the evaluation of the diseased, normal intracranial pressure and lumbar cerebrospinal fluid pressure remain sparsely documented. Intracranial pressure is different from lumbar cerebrospinal fluid pressure. In addition, intracranial pressure differs considerably according to the body position of the patient. Despite this, the current reference values do not distinguish between intracranial and lumbar cerebrospinal fluid pressures, and body position-dependent reference values do not exist. In this study, we aim to establish these reference values. Method A systematic search was conducted in MEDLINE, EMBASE, CENTRAL, and Web of Sciences. Methodological quality was assessed using an amended version of the Joanna Briggs Quality Appraisal Checklist. Intracranial pressure and lumbar cerebrospinal fluid pressure were independently evaluated and subdivided into body positions. Quantitative data were presented with mean ± SD, and 90% reference intervals. Results Thirty-six studies were included. Nine studies reported values for intracranial pressure, while 27 reported values for the lumbar cerebrospinal fluid pressure. Reference values for intracranial pressure were − 5.9 to 8.3 mmHg in the upright position and 0.9 to 16.3 mmHg in the supine position. Reference values for lumbar cerebrospinal fluid pressure were 7.2 to 16.8 mmHg and 5.7 to 15.5 mmHg in the lateral recumbent position and supine position, respectively. Conclusions This systematic review is the first to provide position-dependent reference values for intracranial pressure and lumbar cerebrospinal fluid pressure. Clinically applicable reference values for normal lumbar cerebrospinal fluid pressure were established, and are in accordance with previously used reference values. For intracranial pressure, this study strongly emphasizes the scarcity of normal pressure measures, and highlights the need for further research on the matter.

Abstract Background Cerebral vasospasm (VS) and delayed cerebral ischemia (DCI) constitute major complications following subarachnoid hemorrhage (SAH). A few studies have examined the relationship between different indices of cerebrovascular dynamics with the occurrence of VS. However, their potential association with the development of DCI remains elusive. In this study, we investigated the pattern of changes of different transcranial Doppler (TCD)-derived indices of cerebrovascular dynamics during vasospasm in patients suffering from subarachnoid hemorrhage, dichotomized by the presence of delayed cerebral ischemia. Methods A retrospective analysis was performed using recordings from 32 SAH patients, diagnosed with VS. Patients were divided in two groups, depending on development of DCI. Magnitude of slow waves (SWs) of cerebral blood flow velocity (CBFV) was measured. Cerebral autoregulation was estimated using the moving correlation coefficient Mxa. Cerebral arterial time constant (tau) was expressed as the product of resistance and compliance. Complexity of CBFV was estimated through measurement of sample entropy (SampEn). Results In the whole population (N = 32), magnitude of SWs of ipsilateral to VS side CBFV was higher during vasospasm (4.15 ± 1.55 vs before: 2.86 ± 1.21 cm/s, p

Post-concussion syndrome (PCS) refers to a constellation of physical, cognitive, and emotional symptoms after traumatic brain injury (TBI). Despite its incidence and impact, the underlying mechanisms of PCS are unclear. We hypothesized that impaired cerebral autoregulation (CA) is a contributor. In this article, we present our protocol for non-invasively assessing CA in patients with TBI and PCS in a real-world clinical setting. A prospective, observational study was integrated into outpatient clinics at a tertiary neurosurgical center. Data points included: demographics, symptom profile (Post-Concussion Symptom Scale [PCSS]) and neuropsychological assessment (Cambridge Neuropsychological Test Automated-Battery [CANTAB]). Cerebrovascular metrics (nMxa co-efficient and the transient hyperaemic-response ratio [THRR]) were collected using transcranial Doppler (TCD), finger plethysmography, and bespoke software (ICM+). Twelve participants were initially recruited but 2 were excluded after unsuccessful insonation of the middle cerebral artery (MCA); 10 participants (5 patients with TBI, 5 healthy controls) were included in the analysis (median age 26.5 years, male to female ratio: 7:3). Median PCSS scores were 6/126 for the TBI patient sub-groups. Median CANTAB percentiles were 78 (healthy controls) and 25 (TBI). nMxa was calculated for 90% of included patients, whereas THRR was calculated for 50%. Median study time was 127.5?min and feedback (n?=?6) highlighted the perceived acceptability of the study. This pilot study has demonstrated a reproducible assessment of PCS and CA metrics (non-invasively) in a real-world setting. This protocol is feasible and is acceptable to participants. By scaling this methodology, we hope to test whether CA changes are correlated with symptomatic PCS in patients post-TBI.

Abstract Background After traumatic brain injury (TBI), brain tissue can be further damaged when cerebral autoregulation is impaired. Managing cerebral perfusion pressure (CPP) according to computed “optimal CPP” values based on cerebrovascular reactivity indices might contribute to preventing such secondary injuries. In this study, we examined the discriminative value of a low-resolution long pressure reactivity index (LPRx) and its derived “optimal CPP” in comparison to the well-established high-resolution pressure reactivity index (PRx). Methods Using the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study dataset, the association of LPRx (correlation between 1-min averages of intracranial pressure and arterial blood pressure over a moving time frame of 20 min) and PRx (correlation between 10-s averages of intracranial pressure and arterial blood pressure over a moving time frame of 5 min) to outcome was assessed and compared using univariate and multivariate regression analysis. “Optimal CPP” values were calculated using a multi-window algorithm that was based on either LPRx or PRx, and their discriminative ability was compared. Results LPRx and PRx were both significant predictors of mortality in univariate and multivariate regression analysis, but PRx displayed a higher discriminative ability. Similarly, deviations of actual CPP from “optimal CPP” values calculated from each index were significantly associated with outcome in univariate and multivariate analysis. “Optimal CPP” based on PRx, however, trended towards more precise predictions. Conclusions LPRx and its derived “optimal CPP” which are based on low-resolution data were significantly associated with outcome after TBI. However, they did not reach the discriminative ability of the high-resolution PRx and its derived “optimal CPP.” Nevertheless, LPRx might still be an interesting tool to assess cerebrovascular reactivity in centers without high-resolution signal monitoring. Trial registration ClinicalTrials.gov Identifier: NCT02210221 . First submitted July 29, 2014. First posted August 6, 2014.

Abstract Background Post-traumatic hydrocephalus (PTH) is potentially under-diagnosed and under-treated, generating the need for a more efficient diagnostic tool. We aim to report CSF dynamics of patients with post-traumatic ventriculomegaly. Materials and methods We retrospectively analysed post-traumatic brain injury (TBI) patients with ventriculomegaly who had undergone a CSF infusion test. We calculated the resistance to CSF outflow (Rout), AMP (pulse amplitude of intracranial pressure, ICP), dAMP (AMPplateau-AMPbaseline) and compensatory reserve index correlation coefficient between ICP and AMP (RAP). To avoid confounding factors, included patients had to be non-decompressed or with cranioplasty > 1 month previously and Rout > 6 mmHg/min/ml. Compliance was assessed using the elasticity coefficient. We also compared infusion-tested TBI patients selected for shunting versus those not selected for shunting (consultant decision based on clinical and radiological assessment and the infusion results). Finally, we used data from a group of shunted idiopathic Normal Pressure Hydrocephalus (iNPH) patients for comparison. Results Group A consisted of 36 patients with post-traumatic ventriculomegaly and Group B of 45 iNPH shunt responders. AMP and dAMP were significantly lower in Group A than B (0.55 ± 0.39 vs 1.02 ± 0.72; p

Introduction: Neurocognitive problems associated with posttraumatic stress disorder (PTSD) can interact with impairment resulting from traumatic brain injury (TBI). Research question: We aimed to identify neurocognitive problems associated with probable PTSD following TBI in a civilian sample. Material and methods: The study is part of the CENTER-TBI project (Collaborative European Neurotrauma Effectiveness Research) that aims to better characterize TBI. For this cross-sectional study, we included patients of all severities aged over 15, and a Glasgow Outcome Score Extended (GOSE) above 3. Participants were assessed at six months post-injury on the PTSD Checklist-5 (PCL-5), the Trail Making Test (TMT), the Rey Auditory Verbal Learning Test (RAVLT) and the Cambridge Neuropsychological Test Automated Battery (CANTAB). Primary analysis was a complete case analysis. Regression analyses were performed to investigate the association between the PCL-5 and cognition. Results: Of the 1134 participants included in the complete case analysis, 13.5% screened positive for PTSD. Probable PTSD was significantly associated with higher TMT-(B-A) (OR ​= ​1.35, 95% CI: 1.14–1.60, p ​

Introduction: Common consequences following aneurysmal subarachnoid hemorrhage (aSAH) are cerebral vasospasm (CV), impaired cerebral autoregulation (CA), and disturbance in the autonomic nervous system, as indicated by lower baroreflex sensitivity (BRS). The compensatory interaction between BRS and CA has been shown in healthy volunteers and stable pathological conditions such as carotid atherosclerosis. The aim of this study was to investigate whether the inverse correlation between BRS and CA would be lost in patients after aSAH during vasospasm. A secondary objective was to analyze the time-trend of BRS after aSAH.Materials and Methods: Retrospective analysis of prospectively collected data was performed at the Neuro-Critical Care Unit of Addenbrooke's Hospital (Cambridge, UK) between June 2010 and January 2012. The cerebral blood flow velocity (CBFV) was measured in the middle cerebral artery using transcranial Doppler ultrasonography (TCD). The arterial blood pressure (ABP) was monitored invasively through an arterial line. CA was quantified by the correlation coefficient (Mxa) between slow oscillations in ABP and CBFV. BRS was calculated using the sequential cross-correlation method using the ABP signal.Results: A total of 73 patients with aSAH were included. The age [median (lower-upper quartile)] was 58 (50–67). WFNS scale was 2 (1–4) and the modified Fisher scale was 3 (1–3). In the total group, 31 patients (42%) had a CV and 42 (58%) had no CV. ABP and CBFV were higher in patients with CV during vasospasm compared to patients without CV (p = 0.001 and p < 0.001). There was no significant correlation between Mxa and BRS in patients with CV, neither during nor before vasospasm. In patients without CV, a significant, although moderate correlation was found between BRS and Mxa (rS = 0.31; p = 0.040), with higher BRS being associated with worse CA. Multiple linear regression analysis showed a significant worsening of BRS after aSAH in patients with CV (Rp = −0.42; p < 0.001).Conclusions: Inverse compensatory correlation between BRS and CA was lost in patients who developed CV after aSAH, both before and during vasospasm. The impact of these findings on the prognosis of aSAH should be investigated in larger studies.

Neuromonitoring-derived indices play an important role in implementing personalised medicine for traumatic brain injury patients. A well-established example is the pressure reactivity index (PRx), calculated from spontaneous fluctuations of arterial blood pressure (ABP) and intracranial pressure (ICP). PRx assumes causal relationship between ABP and ICP but lacks the check for this assumption. Granger causality (GC) — a method of assessing causal interactions between time series data — is gaining popularity in neurosciences. In our work, we used ABP and ICP data recorded at the frequency of 100 Hz or higher from 235 traumatic brain injury patients. We focused on time domain GC. Analysis was first performed directly on high-resolution data, which included pulse waves. We showed that due to the measurement delay in high-resolution ABP data, GC analysis may erroneously indicate strong ICP→ABP causal relation. Subsequently, the data were downsampled to 0.1 Hz, effectively removing pulse and respiratory waves. We aimed to investigate how different ways of calculating GC influence results and which way should be recommended for ABP-ICP recordings. We considered aspects like selecting autoregressive model order and dealing with data non-stationarity. In addition, we generated simulated signals to investigate the influence of gaps and different procedures of missing data imputation on GC estimation. We showed that unlike methods which interpolate missing data, replacing missing data by white Gaussian noise did not increase the rate of false GC detection. Python source code used in this study is available at: https://github.com/m-m-placek/python-icmplus-granger-causality. Statement of significance: Assessing causality between time series data is of particular interest when neuromonitoring indices are derived from those time series and causal interaction between them is assumed. Causality assessment can improve reliability of such indices and open pathways for their safe clinical implementation. Granger Causality (GC) has recently been investigated in data collected from traumatic brain injury patients. However, there are two main issues related to applications suggested in these studies. Firstly, they considered GC for entire multi-day data recordings or for 24-h long episodes. There is interest in considering causal relationships in finer granularity, also in terms of their potential real-time applications at the bedside. Secondly, GC calculation requires selecting some parameters and there is no unique nor standardised way of doing that. Many papers often provide very brief description of data pre-processing and GC calculation. For this reason, it can be harder to reproduce and compare results derived from GC application. Different ways of obtaining GC may potentially lead to inconsistent results. Here, we attempted to explore possibility of time-varying GC of finer granularity and to provide general guidelines for application of GC to neurocritical care time series affected by periods of missing values.

Intracranial hypertension and adequacy of brain blood flow are primary concerns following traumatic brain injury. Intracranial pressure (ICP) monitoring is a critical diagnostic tool in neurocritical care. However, all ICP sensors, irrespective of design, are subject to systematic and random measurement inaccuracies that can affect patient care if overlooked or disregarded. The wide choice of sensors available to surgeons raises questions about performance and suitability for treatment. This observational study offers a critical review of the clinical and experimental assessment of ICP sensor accuracy and comments on the relationship between actual clinical performance, bench testing, and manufacturer specifications. Critically, on this basis, the study offers guidelines for the selection of ICP monitoring technologies, an important clinical decision. To complement this, a literature review on important ICP monitoring considerations was included. This study utilises illustrative clinical and laboratory material from 1200 TBI patients (collected from 1992 to 2019) to present several important points regarding the accuracy of in vivo implementation of contemporary ICP transducers. In addition, a thorough literature search was performed, with sources dating from 1960 to 2021. Sources considered to be relevant matched the keywords: “intraparenchymal ICP sensors”, “fiberoptic ICP sensors”, “piezoelectric strain gauge sensors”, “external ventricular drains”, “CSF reference pressure”, “ICP zero drift”, and “ICP measurement accuracy”. Based on single centre observations and the 76 sources reviewed in this paper, this material reports an overall anticipated measurement accuracy for intraparenchymal transducers of around ± 6.0 mm Hg with an average zero drift of

Introduction: The role of near-infrared spectroscopy (NIRS) for the evaluation of cerebral haemodynamics is gaining increasing popularity because of its noninvasive nature. The aim of this study was to evaluate the role of the integral components of regional cerebral oxygenation (rSO2) measured by NIRS [i.e., arterial-oxyhemoglobin (O2Hbi) and venous-deoxyhemoglobin (HHbi)-components], as indirect surrogates of cerebral blood flow (CBF) in a cohort of critically ill patients with coronavirus disease 2019 (COVID-19). We compared these findings to the gold standard technique for noninvasive CBF assessment, Transcranial Doppler (TCD).Methods: Mechanically ventilated patients with COVID-19 admitted to the Intensive Care Unit (ICU) of Policlinico San Martino Hospital, Genova, Italy, who underwent multimodal neuromonitoring (including NIRS and TCD), were included. rSO2 and its components [relative changes in O2Hbi, HHbi, and total haemoglobin (cHbi)] were compared with TCD (cerebral blood flow velocity, CBFV). Changes (Δ) in CBFV and rSO2, ΔO2Hbi, ΔHHbi, and ΔcHbi after systemic arterial blood pressure (MAP) modifications induced by different manoeuvres (e.g., rescue therapies and haemodynamic manipulation) were assessed using mixed-effect linear regression analysis and repeated measures correlation coefficients. All values were normalised as percentage changes from the baseline (Δ%).Results: One hundred and four measurements from 25 patients were included. Significant effects of Δ%MAP on Δ%CBF were observed after rescue manoeuvres for CBFV, ΔcHbi, and ΔO2Hbi. The highest correlation was found between ΔCBFV and ΔΔO2Hbi (R = 0.88, p < 0.0001), and the poorest between ΔCBFV and ΔΔHHbi (R = 0.34, p = 0.002).Conclusions: ΔO2Hbi had the highest accuracy to assess CBF changes, reflecting its role as the main component for vasomotor response after changes in MAP. The use of indexes derived from the different components of rSO2 can be useful for the bedside evaluation of cerebral haemodynamics in mechanically ventilated patients with COVID-19.

Introduction: Cerebral autoregulation (CA) plays a fundamental role in the maintenance of adequate cerebral blood flow (CBF). CA monitoring, through direct and indirect techniques, may guide an appropriate therapeutic approach aimed at improving CBF and reducing neurological complications; so far, the role of CA has been investigated mainly in brain-injured patients. The aim of this study is to investigate the role of CA in non-brain injured patients.Methods: A systematic consultation of literature was carried out. Search terms included: “CA and sepsis,” “CA and surgery,” and “CA and non-brain injury.”Results: Our research individualized 294 studies and after screening, 22 studies were analyzed in this study. Studies were divided in three groups: CA in sepsis and septic shock, CA during surgery, and CA in the pediatric population. Studies in sepsis and intraoperative setting highlighted a relationship between the incidence of sepsis-associated delirium and impaired CA. The most investigated setting in the pediatric population is cardiac surgery, but the role and measurement of CA need to be further elucidated.Conclusion: In non-brain injured patients, impaired CA may result in cognitive dysfunction, neurological damage, worst outcome, and increased mortality. Monitoring CA might be a useful tool for the bedside optimization and individualization of the clinical management in this group of patients.

Background: Coronavirus disease 2019 (COVID-19) patients are at high risk of neurological complications consequent to several factors including persistent hypotension. There is a paucity of data on the effects of therapeutic interventions designed to optimize systemic hemodynamics on cerebral autoregulation (CA) in this group of patients.Methods: Single-center, observational prospective study conducted at San Martino Policlinico Hospital, Genoa, Italy, from October 1 to December 15, 2020. Mechanically ventilated COVID-19 patients, who had at least one episode of hypotension and received a passive leg raising (PLR) test, were included. They were then treated with fluid challenge (FC) and/or norepinephrine (NE), according to patients' clinical conditions, at different moments. The primary outcome was to assess the early effects of PLR test and of FC and NE [when clinically indicated to maintain adequate mean arterial pressure (MAP)] on CA (CA index) measured by transcranial Doppler (TCD). Secondary outcomes were to evaluate the effects of PLR test, FC, and NE on systemic hemodynamic variables, cerebral oxygenation (rSo2), and non-invasive intracranial pressure (nICP).Results: Twenty-three patients were included and underwent PLR test. Of these, 22 patients received FC and 14 were treated with NE. The median age was 62 years (interquartile range = 57–68.5 years), and 78% were male. PLR test led to a low CA index [58% (44–76.3%)]. FC and NE administration resulted in a CA index of 90.8% (74.2–100%) and 100% (100–100%), respectively. After PLR test, nICP based on pulsatility index and nICP based on flow velocity diastolic formula was increased [18.6 (17.7–19.6) vs. 19.3 (18.2–19.8) mm Hg, p = 0.009, and 12.9 (8.5–18) vs. 15 (10.5–19.7) mm Hg, p = 0.001, respectively]. PLR test, FC, and NE resulted in a significant increase in MAP and rSo2.Conclusions: In mechanically ventilated severe COVID-19 patients, PLR test adversely affects CA. An individualized strategy aimed at assessing both the hemodynamic and cerebral needs is warranted in patients at high risk of neurological complications.

Traumatic brain injury (TBI) is a major cause of death and disability, particularly amongst young people. Current intensive care management of TBI patients is targeted at maintaining normal brain physiology and preventing secondary injury. Microdialysis is an invasive monitor that permits real-time assessment of derangements in cerebral metabolism and responses to treatment. We examined the prognostic value of microdialysis parameters, and the inter-relationships with other neuromonitoring modalities to identify interventions that improve metabolism. This was an analysis of prospective data in 619 adult TBI patients requiring intensive care treatment and invasive neuromonitoring at a tertiary UK neurosciences unit. Patients had continuous measurement of intracranial pressure (ICP), arterial blood pressure (ABP), brain tissue oxygenation (PbtO2), and cerebral metabolism and were managed according to a standardized therapeutic protocol. Microdialysate was assayed hourly for metabolites including glucose, pyruvate, and lactate. Cerebral perfusion pressure (CPP) and cerebral autoregulation (PRx) were derived from the ICP and ABP. Outcome was assessed with the Glasgow Outcome Score (GOS) at 6 months. Relationships between monitoring variables was examined with generalized additive mixed models (GAMM). Lactate/Pyruvate Ratio (LPR) over the first 3 to 7 days following injury was elevated amongst patients with poor outcome and was an independent predictor of ordinal GOS (p70mmHg, PRx 18mmHg, and brain glucose >1mM. Deranged cerebral metabolism is an important determinant of patient outcome following TBI. Variations in cerebral perfusion, oxygenation and glucose supply are associated with changes in cerebral LPR and suggest therapeutic interventions to improve cerebral metabolism. Future prospective studies are required to determine the efficacy of these strategies.

The measurement of optic nerve sheath diameter (ONSD) has been reported as a non-invasive marker for intracranial pressure (ICP). Nevertheless, it is uncertain whether possible ONSD differences occur with age and sex in healthy and brain-injured populations. The aim of this study was to investigate the effects of sex and age on ONSD in healthy volunteers and patients with traumatic brain injury. We prospectively included 122 healthy adult volunteers (Galliera Hospital, Genova, Italy), and compared age/sex dependence of ONSD to 95 adult patients (Addenbrooke's Hospital, Cambridge, UK) with severe traumatic brain injury (TBI) requiring intubation and invasive ICP monitoring. The two groups were stratified for sex and age. Age was divided into 3 subgroups: (1) young adults: 18–44 years; (2) middle-aged adults: 45–64 years; (3) old adults: >65 years. In healthy volunteers, ONSD was significantly different between males and females [median (interquartile range): 4.2 (3.9–4.6) mm vs. 4.1 (3.6–4.2) mm (p = 0.01), respectively] and was correlated with age (R = 0.50, p < 0.0001). ONSD was significantly increased in group 3 compared to groups 2 and 1, indicating that ONSD values are higher in elderly subjects. In TBI patients, no differences in ONSD were found for sex and the correlation between ONSD and age was non-significant (R = 0.13, p = 0.20). ONSD increases with age and is significantly larger for males in healthy volunteers but not in TBI patients. Different ONSD cut-off values need not be age- or sex-adjusted for the assessment of increased ICP in TBI patients.

Apart from peculiarities of the cerebral circulation, required to perfuse the brain with the subject erect, the principles established for function of the human systemic circulation (pulsatile flow at input and steady flow at output in capillaries) are identical to those established for other mammals. Assumption of the erect posture first as Homo erectus, then as Homo sapiens, conferred huge advantage to humans and led to command of the mammalian kingdom. But this required a circulation which could perfuse the brain securely against gravity in all positions of the body. This review covers what presently is known about the human cerebral circulation, and how such knowledge can be applied in some clinical conditions including development of dementia in older subjects, and in management of patients with elevation of intra-cranial pressure in younger subjects.

It is well known that exposure to microgravity in astronauts leads to a plethora physiological responses such as headward fluid shift, body unloading, and cardiovascular deconditioning. When astronauts return to Earth, some encounter problems related to orthostatic intolerance. An impaired cerebral autoregulation (CA), which could be compromised by the effects of microgravity, has been proposed as one of the mechanisms responsible for orthostatic intolerance. CA is a homeostatic mechanism that maintains cerebral blood flow for any variations in cerebral perfusion pressure by adapting the vascular tone and cerebral vessel diameter. The ground-based models of microgravity are useful tools for determining the gravitational impact of spaceflight on human body. The head-down tilt bed rest (HDTBR), where the subject remains in supine position at −6 degrees for periods ranging from few days to several weeks is the most commonly used ground-based model of microgravity for cardiovascular deconditioning. head-down bed rest (HDBR) is able to replicate cephalic fluid shift, immobilization, confinement, and inactivity. Dry immersion (DI) model is another approach where the subject remains immersed in thermoneutral water covered with an elastic waterproof fabric separating the subject from the water. Regarding DI, this analog imitates absence of any supporting structure for the body, centralization of body fluids, immobilization and hypokinesia observed during spaceflight. However, little is known about the impact of microgravity on CA. Here, we review the fundamental principles and the different mechanisms involved in CA. We also consider the different approaches in order to assess CA. Finally, we focus on the effects of short- and long-term spaceflight on CA and compare these findings with two specific analogs to microgravity: HDBR and DI.

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 ± 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels.

A reliable method for non-invasive detection of dangerous intracranial pressure (ICP) elevations is still unavailable. In this preliminary study, we investigate quantitatively our observation that superimposing waveforms of transcranial Doppler blood flow velocity (FV) and arterial blood pressure (ABP) may help in non-invasive identification of ICP plateau waves. Recordings of FV, ABP and ICP in 160 patients with severe head injury (treated in the Neurocritical Care Unit at Addenbrookes Hospital, Cambridge, UK) were reviewed retrospectively. From that cohort, we identified 18 plateau waves registered in eight patients. A “measure of dissimilarity” (Dissimilarity/Difference Index, DI) between ABP and FV waveforms was calculated in three following steps: 1. fragmentation of ABP and FV signal according to cardiac cycle; 2. obtaining the normalised representative ABP and FV cycles; and finally; 3. assessing their difference, represented by the area between both curves. DI appeared to discriminate ICP plateau waves from baseline episodes slightly better than conventional pulsatility index did: area under ROC curve 0.92 vs. 0.90, sensitivity 0.81 vs. 0.69, accuracy 0.88 vs. 0.84, respectively. The concept of DI, if further tested and improved, might be used for non-invasive detection of ICP plateau waves.

Abstract Background We present a multiplex network model for the analysis of Intracranial Pressure (ICP) and Heart Rate (HR) behaviour after severe brain traumatic injuries in pediatric patients. The ICP monitoring is of vital importance for checking life threathening conditions, and understanding the behaviour of these parameters is crucial for a successful intervention of the clinician. Our own observations, exhibit cross-talks interaction events happening between HR and ICP, i.e. transients in which both the ICP and the HR showed an increase of 20% with respect to their baseline value in the window considered. We used a complex event processing methodology, to investigate the relationship between HR and ICP, after traumatic brain injuries (TBI). In particular our goal has been to analyse events of simultaneous increase by HR and ICP (i.e. cross-talks), modelling the two time series as a unique multiplex network system (Lacasa et al., Sci Rep 5:15508-15508, 2014). Methods and data We used a complex network approach based on visibility graphs (Lacasa et al., Sci Rep 5:15508-15508, 2014) to model and study the behaviour of our system and to investigate how and if network topological measures can give information on the possible detection of crosstalks events taking place in the system. Each time series was converted as a layer in a multiplex network. We therefore studied the network structure, focusing on the behaviour of the two time series in the cross-talks events windows detected. We used a dataset of 27 TBI pediatric patients, admitted to Addenbrooke’s Hospital, Cambridge, Pediatric Intensive Care Unit (PICU) between August 2012 and December 2014. Results Following a preliminary statistical exploration of the two time series of ICP and HR, we analysed the multiplex network proposed, focusing on two standard topological network metrics: the mutual interaction, and the average edge overlap (Lacasa et al., Sci Rep 5:15508-15508, 2014). We compared results obtained for these two indicators, considering windows in which a cross talks event between HR and ICP was detected with windows in which cross talks events were not present. The analysis of such metrics gave us interesting insights on the time series behaviour. More specifically we observed an increase in the value of the mutual interaction in the case of cross talk as compared to non cross talk. This seems to suggest that mutual interaction could be a potentially interesting “marker” for cross talks events.

Head-down bed rest (HDBR) is commonly considered as ground-based analog to spaceflight and simulates the headward fluid shift and cardiovascular deconditioning associated with spaceflight. We investigated in healthy volunteers whether HDBR, with or without countermeasures, affect cerebral autoregulation (CA). Twelve men (at selection: 34 ± 7 years; 176 ± 7 cm; 70 ± 7 kg) underwent three interventions of a 21-day HDBR: a control condition without countermeasure (CON), a condition with resistance vibration exercise (RVE) comprising of squats, single leg heel, and bilateral heel raises and a condition using also RVE associated with nutritional supplementation (NeX). Cerebral blood flow velocity was assessed using transcranial Doppler ultrasonography. CA was evaluated by transfer function analysis and by the autoregulatory index (Mxa) in order to determine the relationship between mean cerebral blood flow velocity and mean arterial blood pressure. In RVE condition, coherence was increased after HDBR. In CON condition, Mxa index was significantly reduced after HDBR. In contrast, in RVE and NeX conditions, Mxa were increased after HBDR. Our results indicate that HDBR without countermeasures may improve dynamic CA, but this adaptation may be dampened with RVE. Furthermore, nutritional supplementation did not enhance or worsen the negative effects of RVE. These findings should be carefully considered and could not be applied in spaceflight. Indeed, the subjects spent their time in supine position during bed rest, unlike the astronauts who perform normal daily activities.

Normal pressure hydrocephalus (NPH) is a syndrome comprising gait disturbance, cognitive decline and urinary incontinence that is an unique model of reversible brain injury, but it presents as a challenging spectrum of disease cohorts. Diffusion Tensor Imaging (DTI), with its ability to interrogate structural white matter patterns at a microarchitectural level, is a potentially useful tool for the confirmation and characterization of disease cohorts at the clinical-research interface. However, obstacles to its widespread use involve the need for consistent DTI analysis and interpretation tools across collaborator sites. We present the use of DTI profiles, a simplistic methodology to interpret white matter injury patterns based on the morphology of diffusivity parameters. We examined 13 patients with complex NPH, i.e., patients with NPH and overlay from multiple comorbidities, including vascular risk burden and neurodegenerative disease, undergoing extended CSF drainage, clinical assessments, and multi-modal MR imaging. Following appropriate exclusions, we compared the morphology of DTI profiles in such complex NPH patients (n = 12, comprising 4 responders and 8 non-responders) to exemplar DTI profiles from a cohort of classic NPH patients (n = 16) demonstrating responsiveness of white matter injury to ventriculo-peritoneal shunting. In the cohort of complex NPH patients, mean age was 71.3 ± 7.6 years (10 males, 2 females) with a mean MMSE score of 21.1. There were 5 age-matched healthy controls, mean age was 73.4 ± 7.2 years (1 male, 4 females) and mean MMSE score was 26.8. In the exemplar cohort of classic NPH patients, mean age was 74.7 ± 5.9 years (10 males, 6 females) and mean MMSE score was 24.1. There were 9 age-matched healthy controls, mean age was 69.4 ± 9.7 years (4 males, 5 females) and mean MMSE score was 28.6. We found that, despite the challenges of acquiring DTI metrics from differing scanners across collaborator sites and NPH patients presenting as differing cohorts along the spectrum of disease, DTI profiles for responsiveness to interventions were comparable. Distinct DTI characteristics were demonstrated for complex NPH responders vs. non-responders. The morphology of DTI profiles for complex NPH responders mimicked DTI patterns found in predominantly shunt-responsive patients undergoing intervention for classic NPH. However, DTI profiles for complex NPH non-responders was suggestive of atrophy. Our findings suggest that it is possible to use DTI profiles to provide a methodology for rapid description of differing cohorts of disease at the clinical-research interface. By describing DTI measures morphologically, it was possible to consistently compare white matter injury patterns across international collaborator datasets.

Radiological assessment of the head is a routine part of the management of traumatic brain injury. This assessment can help to determine the requirement for invasive intracranial pressure (ICP) monitoring. The radiological correlates of elevated ICP have been widely studied in adults but far fewer specific pediatric studies have been conducted. There is, however, growing evidence that there are important differences in the radiological presentations of elevated ICP between children and adults; a reflection of the anatomical and physiological differences, as well as a difference in the pathophysiology of brain injury in children. Here in, we review the radiological parameters that correspond with increased ICP in children that have been described in the literature. We then describe the future directions of this work and our recommendations in order to develop non-invasive and radiological markers of raised ICP in children.