Publications by authors named "Frederick A Zeiler"

114 Publications

Transcranial Doppler Based Cerebrovascular Reactivity Indices in Adult Traumatic Brain Injury: A Scoping Review of Associations With Patient Oriented Outcomes.

Front Pharmacol 2021 6;12:690921. Epub 2021 Jul 6.

Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Disruption in cerebrovascular reactivity following traumatic brain injury (TBI) is a known phenomenon that may hold prognostic value and clinical relevance. Ultimately, improved knowledge of this process and more robust means of continuous assessment may lead to advances in precision medicine following TBI. One such method is transcranial Doppler (TCD), which has been employed to evaluate cerebrovascular reactivity following injury utilizing a continuous time-series approach. The present study undertakes a scoping review of the literature on the association of continuous time-domain TCD based indices of cerebrovascular reactivity, with global functional outcomes, cerebral physiologic correlates, and imaging evidence of lesion change. Multiple databases were searched from inception to November 2020 for articles relevant to the association of continuous time-domain TCD based indices of cerebrovascular reactivity with global functional outcomes, cerebral physiologic correlates, and imaging evidence of lesion change. Thirty-six relevant articles were identified. There was significant evidence supporting an association with continuous time-domain TCD based indices and functional outcomes following TBI. Indices based on mean flow velocity, as measured by TCD, were most numerous while more recent studies point to systolic flow velocity-based indices encoding more prognostic utility. Physiologic parameters such as intracranial pressure, cerebral perfusion pressure, Carbon Dioxide (CO2) reactivity as well as more established indices of cerebrovascular reactivity have all been associated with these TCD based indices. The literature has been concentrated in a few centres and is further limited by the lack of multivariate analysis. This systematic scoping review of the literature identifies that there is a substantial body of evidence that cerebrovascular reactivity as measured by time-domain TCD based indices have prognostic utility following TBI. Indices based on mean flow velocities have the largest body of literature for their support. However, recent studies indicate that indices based on systolic flow velocities may contain the most prognostic utility and more closely follow more established measures of cerebrovascular reactivity. To a lesser extent, the literature supports some associations between these indices and cerebral physiologic parameters. These indices provide a more complete picture of the patient's physiome following TBI and may ultimately lead to personalized and precise clinical care. Further validation in multi-institution studies is required before these indices can be widely adopted clinically.
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http://dx.doi.org/10.3389/fphar.2021.690921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290494PMC
July 2021

Non-Invasive Continuous Cerebrovascular Monitoring for Subacute Bedside and Outpatient Settings: An Important Advancement.

Neurotrauma Rep 2021 20;2(1):25-26. Epub 2021 Jan 20.

Section of Neurosurgery, Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada.

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http://dx.doi.org/10.1089/neur.2020.0064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240829PMC
January 2021

Cerebrovascular Response to Phenylephrine in Traumatic Brain Injury: A Scoping Systematic Review of the Human and Animal Literature.

Neurotrauma Rep 2020 23;1(1):46-62. Epub 2020 Jul 23.

Biomedical Engineering, University of Manitoba, Winnipeg, Manitoba, Canada.

Intravenous phenylephrine (PE) is utilized commonly in critical care for cardiovascular support. Its impact on the cerebrovasculature is unclear and its use may have important implications during states of critical neurological illness. The aim of this study was to perform a scoping review of the literature on the cerebrovascular/cerebral blood flow (CBF) effects of PE in traumatic brain injury (TBI), evaluating both animal models and human studies. We searched MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and the Cochrane Library from inception to January 2020. We identified 12 studies with various animal models and 4 studies in humans with varying TBI pathology. There was a trend toward a consistent increase in mean arterial pressure (MAP) by the injection of PE systemically, and by proxy, an increase of the cerebral perfusion pressure (CPP). There was a consistent constriction of cerebral vessels by PE reported in the small number of studies documenting such a response. However, the heterogeneity of the literature on the CBF/cerebral blood volume (CBV) response makes the strength of the conclusions on PE limited. Studies were heterogeneous in design and had significant limitations, with most failing to adjust for confounding factors in cerebrovascular/CBF response. This review highlights the significant knowledge gap on the cerebrovascular/CBF effects of PE administration in TBI, calling for further study on the impact of PE on the cerebrovasculature both and in experimental settings.
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http://dx.doi.org/10.1089/neur.2020.0008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240891PMC
July 2020

Antithrombotic choice in blunt cerebrovascular injuries: Experience at a tertiary trauma center, systematic review, and meta-analysis.

J Trauma Acute Care Surg 2021 Jul;91(1):e1-e12

From the Division of Neurosurgery (J.C.K., S.M.P., F.M., S.T., C.R.P., V.X.D.Y., L.d.C.), Sunnybrook Health Sciences Centre, University of Toronto, Toronto; Health Sciences North, Division of Neurosurgery (S.M.P.), Northern Ontario School of Medicine, Sudbury, ON; Biomedical Engineering, Faculty of Engineering (F.A.Z.), Department of Anatomy and Cell Science, Rady Faculty of Health Sciences (F.A.Z.), and Centre on Aging (F.A.Z.), University of Manitoba, Winnipeg, MA, Canada; Division of Anaesthesia, Department of Medicine (F.A.Z.), Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; and Sunnybrook Health Sciences Centre, Department of Medical Imaging (M.M.), Sunnybrook Health Sciences Centre, Department of Surgery (A.N.), and Department of Medical Imaging, Sunnybrook Health Sciences Centre (L.d.C.), University of Toronto, Toronto, ON, Canada.

Background: Blunt cerebrovascular injuries (BCVIs) may occur following trauma and lead to ischemic stroke if untreated. Antithrombotic therapy decreases this risk; however, the optimal agent has yet to be determined in this population. The aim of this study was to compare the risk-benefit profile of antiplatelet (AP) versus anticoagulant (AC) therapy in rates of ischemic stroke and hemorrhagic complications in BCVI patients.

Methods: We performed a retrospective review of BCVI patients at our tertiary care Trauma hospital from 2010 to 2015, and a systematic review and meta-analysis of the literature. The OVID Medline, Embase, Web of Science, and Cochrane Library databases were searched from inception to September 16, 2019. References of included publications were searched manually for other relevant articles. The search was limited to articles in humans, in patients 18 years or older, and in English. Studies that reported treatment-stratified clinical outcomes following AP or AC treatment in BCVI patients were included. Exclusion criteria included case reports, case series with n < 5, review articles, conference abstracts, animal studies, and non-peer-reviewed publications. Data were extracted from each study independently by two reviewers, including study design, country of origin, sex and age of patients, Injury Severity Score, Biffl grade, type of treatment, ischemic stroke rate, and hemorrhage rate. Pooled estimates using odds ratio (OR) were combined using a random-effects model using a Mantel-Hanzel weighting. The main outcome of interest was rate of ischemic stroke due to BCVI, and the secondary outcome was hemorrhage rate based on AC or AP treatment.

Results: In total, there were 2044 BCVI patients, as reported in the 22 studies in combination with our institutional data. The stroke rate was not significantly different between the two treatment groups (OR, 1.27; 95% confidence interval, 0.40-3.99); however, the hemorrhage rate was decreased in AP versus AC treated groups (OR, 0.38; 95% confidence interval, 0.15-1.00).

Conclusion: Based on this meta-analysis, both AC and AP seem similarly effective in preventing ischemic stroke, but AP is better tolerated in the trauma population. This suggests that AP therapy may be preferred, but this should be further assessed with prospective randomized trials.

Level Of Evidence: Review article, level II.
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http://dx.doi.org/10.1097/TA.0000000000003194DOI Listing
July 2021

Early diagnosis of mortality using admission CT perfusion in severe traumatic brain injury patients (ACT-TBI): protocol for a prospective cohort study.

BMJ Open 2021 06 9;11(6):e047305. Epub 2021 Jun 9.

Department of Radiology, University of Manitoba Faculty of Health Sciences, Winnipeg, Manitoba, Canada

Introduction: Severe traumatic brain injury (TBI) is a catastrophic neurological condition with significant economic burden. Early in-hospital mortality (<48 hours) with severe TBI is estimated at 50%. Several clinical examinations exist to determine brain death; however, most are difficult to elicit in the acute setting in patients with severe TBI. Having a definitive assessment tool would help predict early in-hospital mortality in this population. CT perfusion (CTP) has shown promise diagnosing early in-hospital mortality in patients with severe TBI and other populations. The purpose of this study is to validate admission CTP features of brain death relative to the clinical examination outcome for characterizing early in-hospital mortality in patients with severe TBI.

Methods And Analysis: The Early Diagnosis of Mortality using Admission CT Perfusion in Severe Traumatic Brain Injury Patients study, is a prospective cohort study in patients with severe TBI funded by a grant from the Canadian Institute of Health Research. Adults aged 18 or older, with evidence of a severe TBI (Glasgow Coma Scale score ≤8 before initial resuscitation) and, on mechanical ventilation at the time of imaging are eligible. Patients will undergo CTP at the time of first imaging on their hospital admission. Admission CTP compares with the reference standard of an accepted bedside clinical assessment for brainstem function. Deferred consent will be used. The primary outcome is a binary outcome of mortality (dead) or survival (not dead) in the first 48 hours of admission. The planned sample size for achieving a sensitivity of 75% and a specificity of 95% with a CI of ±5% is 200 patients.

Ethics And Dissemination: This study has been approved by the University of Manitoba Health Research Ethics Board. The findings from our study will be disseminated through peer-reviewed journals and presentations at local rounds, national and international conferences. The public will be informed through forums at the end of the study.

Trial Registration Number: NCT04318665.
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http://dx.doi.org/10.1136/bmjopen-2020-047305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191612PMC
June 2021

Point-of-Care Noninvasive Assessments of Cerebrovascular Reactivity in Traumatic Brain Injury: Integrating the Physiome with Clinical Phenotype.

Ann Neurol 2021 Jul 11;90(1):19-21. Epub 2021 May 11.

Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

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http://dx.doi.org/10.1002/ana.26092DOI Listing
July 2021

Lower Limit of Reactivity Assessed with PRx in an Experimental Setting.

Acta Neurochir Suppl 2021 ;131:275-278

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

In traumatic brain injury, longer time spent with a cerebral perfusion pressure (CPP) below the pressure reactivity index (PRx)-derived lower limit of reactivity (LLR) has been shown to be statistically associated with higher mortality. We set out to scrutinise the behaviour of LLR and the methods of its estimation in individual cases by performing retrospective analysis of intracranial pressure (ICP), arterial blood pressure (ABP) and laser Doppler flow (LDF) signals recorded in nine piglets undergoing controlled, terminal hypotension. We focused on the sections of the recordings with stable experimental conditions where a clear breakpoint of LDF/CPP characteristic (LLA) could be identified.In eight of the nine experiments, when CPP underwent a monotonous decrease, the relationship PRx/CPP showed two breakpoints (1 - when PRx starts to rise; 2 - when PRx saturates at PRx > 0.3), with LDF-based LLA sitting between them. LLR (CPP at PRx reaching 0.3 in the error bar chart) was close to the lower LLR breakpoint.In conclusion, when CPP has a monotonous decrease, PRx starts worsening before CPP crosses the LLA. A further decrease in CPP below LLA would cause a decrease in CBF, even if the pressure reactivity is not completely lost. This pattern should be taken into account when PRx is used to detect LLA continuously.
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http://dx.doi.org/10.1007/978-3-030-59436-7_51DOI Listing
June 2021

Methodological Consideration on Monitoring Refractory Intracranial Hypertension and Autonomic Nervous System Activity.

Acta Neurochir Suppl 2021 ;131:211-215

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Refractory intracranial hypertension (RIH) refers to a dramatic increase in intracranial pressure (ICP) that cannot be controlled by treatment and leads to patient death. Detrimental sequelae of raised ICP in acute brain injury (ABI) are unclear because the underlying physiopathological mechanisms of raised ICP have not been sufficiently investigated. Recent reports have shown that autonomic activity is altered during changes in ICP. The aim of our study was to evaluate the feasibility of assessing autonomic activity during RIH with our adopted methodology. We selected 24 ABI patients for retrospective review who developed RIH. They were monitored based on ICP, arterial blood pressure, and electrocardiogram using ICM+ software. Secondary parameters reflecting autonomic activity were computed in time and frequency domains through the continuous measurement of heart rate variability and baroreflex sensitivity. The results of the analysis will be presented later in a full paper. This preliminary analysis shows the feasibility of the adopted methodology.
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http://dx.doi.org/10.1007/978-3-030-59436-7_41DOI Listing
June 2021

Optimal Cerebral Perfusion Pressure Assessed with a Multi-Window Weighted Approach Adapted for Prospective Use: A Validation Study.

Acta Neurochir Suppl 2021 ;131:181-185

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background: Pressure reactivity index (PRx)-cerebral perfusion pressure (CPP) relationships over a given time period can be used to detect a value of CPP at which PRx shows the best autoregulation (optimal CPP, or CPPopt). Algorithms for continuous assessment of CPPopt in traumatic brain injury (TBI) patients reached the desired high yield with a multi-window approach (CPPopt_MA). However, the calculations were tested on retrospective manually cleaned datasets. Moreover, CPPopt false-positive values can be generated from non-physiological variations of intracranial pressure (ICP) and arterial blood pressure (ABP). Therefore, the algorithm robustness was improved, making it suitable for prospective bedside application (COGiTATE trial).

Objective: To validate the CPPopt revised algorithm in a large single-centre retrospective cohort of TBI patients.

Methods: 840 TBI patients were included. CPPopt yield, stability and ability to discriminate outcome groups were compared to CPPopt_MA and the Brain Trauma Foundation (BTF) guideline reference.

Results: CPPopt yield was lower than CPPopt_MA yield (85% and 90%, p < 0.001), but, importantly, with increased stability (p < 0.0001). The ∆(CPP-CPPopt) could distinguish the mortality and survival outcome (t = -6.7, p < 0.0001) with a statistical significance higher than the ∆CPP calculated with the guideline reference (CPP-60) (t = -4.5, p < 0.0001).

Conclusion: This study validates, on a large cohort of patients, the new algorithm proposed for prospective use of CPPopt as a CPP target at bedside.
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http://dx.doi.org/10.1007/978-3-030-59436-7_36DOI Listing
June 2021

Optimal Cerebral Perfusion Pressure Based on Intracranial Pressure-Derived Indices of Cerebrovascular Reactivity: Which One Is Better for Outcome Prediction in Moderate/Severe Traumatic Brain Injury?

Acta Neurochir Suppl 2021 ;131:173-179

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Intracranial pressure (ICP)-derived indices of cerebrovascular reactivity (e.g., PRx, PAx, and RAC) have been developed to improve understanding of brain status from available neuromonitoring variables. These indices are moving correlation coefficients between slow-wave vasogenic fluctuations in ICP and arterial blood pressure. In this retrospective analysis of neuromonitoring data from 200 patients admitted with moderate/severe traumatic brain injury (TBI), we evaluate the predictive value of CPPopt based on these ICP-derived indices of cerebrovascular reactivity. Valid CPPopt values were obtained in 92.3% (PRx), 86.7% (PAX), and 84.6% (RAC) of the monitoring periods, respectively. In multivariate logistic analysis, a baseline model that includes age, sex, and admission Glasgow Coma Score had an area under the receiver operating curve of 0.762 (P < 0.0001) for dichotomous outcome prediction (dead vs. good recovery). When adding time/dose of CPP below CPPopt, all multivariate models (based on PRx, PAx, and RAC) predicted the dichotomous outcome measure, but additional value of the prediction was only significantly added by the PRx-based calculations of time spent with CPP below CPPopt and dose of CPP below CPPopt.
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http://dx.doi.org/10.1007/978-3-030-59436-7_35DOI Listing
June 2021

Patient's Clinical Presentation and CPPopt Availability: Any Association?

Acta Neurochir Suppl 2021 ;131:167-172

Department of Intensive Care, University Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: The 'optimal' CPP (CPPopt) concept is based on the vascular pressure reactivity index (PRx). The feasibility and effectiveness of CPPopt guided therapy in severe traumatic brain injury (TBI) patients is currently being investigated prospectively in the COGiTATE trial. At the moment there is no clear evidence that certain admission and treatment characteristics are associated with CPPopt availability (yield).

Objective: To test the relation between patients' admission and treatment characteristics and the average CPPopt yield.

Methods: Retrospective analysis of 230 patients from the CENTER-TBI high-resolution database with intracranial pressure (ICP) measured using an intraparenchymal probe. CPPopt was calculated using the algorithm set for the COGiTATE study. CPPopt yield was defined as the percentage of CPP monitored time (%) when CPPopt is available. The variables in the statistical model included age, admission Glasgow Coma Scale (GCS), gender, pupil response, hypoxia and hypotension at the scene, Marshall computed tomography (CT) score, decompressive craniectomy, injury severity score score and 24-h therapeutic intensity level (TIL) score.

Results: The median CPPopt yield was 80.7% (interquartile range 70.9-87.4%). None of the selected variables showed a significant statistical correlation with the CPPopt yield.

Conclusion: In this retrospective multicenter study, none of the selected admission and treatment variables were related to the CPPopt yield.
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http://dx.doi.org/10.1007/978-3-030-59436-7_34DOI Listing
June 2021

Usability of Noninvasive Counterparts of Traditional Autoregulation Indices in Traumatic Brain Injury.

Acta Neurochir Suppl 2021 ;131:163-166

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

The pressure reactivity index (PRx) and the pulse amplitude index (PAx) are invasively determined parameters that are commonly used to describe autoregulation following traumatic brain injury (TBI). Using a transcranial Doppler ultrasound (TCD) technique, it is possible to approximate cerebral arterial blood volume (CaBV) solely from cerebral blood flow velocities, and further, to calculate non-invasive markers of autoregulation. In this brief study, we aimed to investigate whether the estimation of relative CaBV with different models could describe the cerebrovascular reactivity of TBI patients. PRx, PAx and their non-invasive counterparts (nPRx and nPAx) were calculated retrospectively from data collected during the monitoring of TBI patients. CaBV, an essential parameter for the calculation of nPRx and nPAx, was determined with both a continuous flow forward (CFF) model-considering a non-pulsatile blood outflow from the brain-and a pulsatile flow forward (PFF) model, presuming a pulsatile outflow. We found that the estimated CaBV demonstrates good coherence with ICP and that nPRx and nPAx can describe cerebrovascular reactivity similarly to PRx and PAx. Continuous monitoring with TCD is difficult, so the usability of PRx and PAx is limited. However, they might become useful for clinicians in the near future owing to rapid advances in these technologies.
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http://dx.doi.org/10.1007/978-3-030-59436-7_33DOI Listing
June 2021

Cerebrovascular Consequences of Elevated Intracranial Pressure After Traumatic Brain Injury.

Acta Neurochir Suppl 2021 ;131:43-48

Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

We compared various descriptors of cerebral hemodynamics in 517 patients with traumatic brain injury (TBI) who had, on average, elevated (>23 mmHg) or normal (<15 mmHg) intracranial pressure (ICP). In a subsample of 193 of those patients, transcranial Doppler ultrasound (TCD) recordings were made. Arterial blood pressure (ABP), cerebral blood flow velocity (CBFV), cerebral autoregulation indices based on TCD (the mean flow index (Mx; the coefficient of correlation between the the cerebral perfusion pressure CPP and flow velocity) and the autoregulation index (ARI)), and the pressure reactivity index (PRx) were compared between groups. We also analyzed the TCD-based cerebral blood flow (CBF) index (diastolic CBFV/mean CBFV), the spectral pulsatility index (sPI), and the critical closing pressure (CrCP). Finally, we also looked at brain tissue oxygenation (cerebral oxygen partial tension (PbtO)) in 109 patients. The mean cerebral perfusion pressure (CPP) was lower in the group with elevated ICP (p < 0.01), despite a higher mean arterial pressure (MAP) (p < 0.005) and worse autoregulation (as assessed with the Mx, ARI, and PRx indices), greater CrCP, a lower CBF index, and a higher sPI (all with p values of <0.001). Neither the mean CBFV nor PbtO reached significant differences between groups. Mortality in the group with elevated ICP was almost three times greater than that in the group with normal ICP (45% versus 17%). Elevated ICP affects cerebral autoregulation. When autoregulation is not working properly, the brain is exposed to ischemic insults whenever CPP falls.
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http://dx.doi.org/10.1007/978-3-030-59436-7_10DOI Listing
June 2021

Visualization of Intracranial Pressure Insults After Severe Traumatic Brain Injury: Influence of Individualized Limits of Reactivity.

Acta Neurochir Suppl 2021 ;131:7-10

Academic Neurosurgery, University of Cambridge, Cambridge, UK.

Cerebral perfusion pressure (CPP) lower limits of reactivity can be determined almost continuously after severe traumatic brain injury (TBI), and deviation below the lower limit carries important prognostic information. In this study, we used a recently derived coloured contour method for visualizing intracranial pressure (ICP) insults to describe the influence of having a CPP above the CPP lower limits of reactivity after severe TBI. In a cohort of 729 patients, we examined the relationship between ICP insults and the 6-month Glasgow Outcome Scale score, using colour-coded plots, as described previously. We then assessed this relationship when ICP insults were above or below the CPP lower limit of reactivity. We found a curvilinear relationship whereby even prolonged durations of low-intensity ICP insults were not associated with poor outcomes but short durations of high-intensity insults were. When only ICP insults with a CPP below the CPP lower limit of reactivity were considered, a much lower intensity of ICP insults could be tolerated. A CPP above the lower limits of reactivity exerts a protective effect, whereas a CPP below the lower reactivity limits renders the patient vulnerable to increased morbidity from intracranial hypertension.
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http://dx.doi.org/10.1007/978-3-030-59436-7_2DOI Listing
June 2021

Genetic Variation and Impact on Outcome in Traumatic Brain Injury: an Overview of Recent Discoveries.

Curr Neurol Neurosci Rep 2021 03 10;21(5):19. Epub 2021 Mar 10.

Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Purpose Of Review: Traumatic brain injury (TBI) has a significant burden of disease worldwide and outcomes vary widely. Current prognostic tools fail to fully account for this variability despite incorporating clinical, radiographic, and biochemical data. This variance could possibly be explained by genotypic differences in the patient population. In this review, we explore single nucleotide polymorphism (SNP) TBI outcome association studies.

Recent Findings: In recent years, SNP association studies in TBI have focused on global, neurocognitive/neuropsychiatric, and physiologic outcomes. While the APOE gene has been the most extensively studied, other genes associated with neural repair, cell death, the blood-brain barrier, cerebral edema, neurotransmitters, mitochondria, and inflammatory cytokines have all been examined for their association with various outcomes following TBI. The results have been mixed across studies and even within genes. SNP association studies provide insight into mechanisms by which outcomes may vary following TBI. Their individual clinical utility, however, is often limited by small sample sizes and poor reproducibility. In the future, they may serve as hypothesis generating for future therapeutic targets.
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http://dx.doi.org/10.1007/s11910-021-01106-1DOI Listing
March 2021

Advanced Bio-signal Analytics for Continuous Bedside Monitoring of Aneurysmal Subarachnoid Hemorrhage: The Future.

Neurocrit Care 2021 04 5;34(2):375-378. Epub 2021 Jan 5.

Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.

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http://dx.doi.org/10.1007/s12028-020-01170-4DOI Listing
April 2021

Hypertonic Saline for Moderate Traumatic Brain Injury: A Scoping Review of Impact on Neurological Deterioration.

Neurotrauma Rep 2020 15;1(1):253-260. Epub 2020 Dec 15.

Section of Neurosurgery, Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada.

Hypertonic saline (HTS) is a commonly administered agent for intracranial pressure (ICP) control in traumatic brain injury (TBI). The literature on its use is mainly in moderate/severe TBI where invasive ICP monitoring is present. The role of HTS in patients with moderate TBI (mTBI) outside of the intensive care unit (ICU) setting remains unclear. The goal of this scoping review was to provide an overview of the available literature on HTS administration in patients with mTBI without ICP monitoring, assessing its impact on outcome and transitions in care. We performed a scoping systematic review of the literature of MEDLINE, Embase, Scopus, BIOSIS, and the Cochrane Databases from inception to July 31, 2020. We searched for those published articles documenting the administration of HTS in patients with mTBI with recorded functional outcome or transitions in hospital care. A two-step review process was conducted in accordance with methodology outlined in the . There were many studies with combined moderate/severe TBI populations. However, most failed to document subgroup analysis for patients with mTBI. Our search strategy identified only one study that documented the administration of HTS in mTBI in which subgroup analysis for mTBI and outcomes were provided. This retrospective cohort study assessed patients with mTBI who did/did not receive prophylactic HTS, finding that those not receiving HTS demonstrated a deterioration in Glasgow Coma Scale (GCS) score in the first 48 h. However, the HTS group did demonstrate a trend to longer hospital stay and pneumonia. Our scoping review identified a significant gap in knowledge surrounding the use of HTS for patients with mTBI without invasive ICP monitoring. The limited identified literature suggests prophylactic administration prevents clinical deterioration, although this is based on a single study with data available for mTBI sub-analysis. Further studies on HTS in non-monitored patients with mTBI are required.
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http://dx.doi.org/10.1089/neur.2020.0056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769038PMC
December 2020

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study.

PLoS One 2020 14;15(12):e0243427. Epub 2020 Dec 14.

Department of Physiology and Pharmacology, Section of Perioperative Medicine and Intensive Care, Karolinska Institutet, Stockholm, Sweden.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243427PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735618PMC
January 2021

Autonomic Nervous System Activity during Refractory Rise in Intracranial Pressure.

J Neurotrauma 2021 Jun 12;38(12):1662-1669. Epub 2021 Jan 12.

Brain Division of Neurosurgery, Department of Clinical Neurosciences, Physics Laboratory, University of Cambridge, Cambridge, United Kingdom.

Refractory intracranial hypertension (RIH) is a dramatic increase in intracranial pressure (ICP) that cannot be controlled by treatment. Recent reports suggest that the autonomic nervous system (ANS) activity may be altered during changes in ICP. Our study aimed to assess ANS activity during RIH and the causal relationship between rising in ICP and autonomic activity. We reviewed retrospectively 24 multicenter (Cambridge, Tromso, Berlin) patients in whom RIH developed as a pre-terminal event after acute brain injury (ABI). They were monitored with ICP, arterial blood pressure (ABP), and electrocardiography (ECG) using ICM+ software. Parameters reflecting autonomic activity were computed in time and frequency domain through the measurement of heart rate variability (HRV) and baroreflex sensitivity (BRS). Our results demonstrated that a rise in ICP was associated to a significant rise in HRV and BRS with a higher significance level in the high-frequency HRV ( < 0.001). This increase was followed by a significant decrease in HRV and BRS above the upper-breakpoint of ICP where ICP pulse-amplitude starts to decrease whereas the mean ICP continues to rise. Temporality measured with a Granger test suggests a causal relationship from ICP to ANS. The above results suggest that a rise in ICP interacts with ANS activity, mainly interfacing with the parasympathetic-system. The ANS seems to react to the rise in ICP with a response possibly focused on maintaining the cerebrovascular homeostasis. This happens until the critical threshold of ICP is reached above which the ANS variables collapse, probably because of low perfusion of the brain and the central autonomic network.
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http://dx.doi.org/10.1089/neu.2020.7091DOI Listing
June 2021

The Impact of Vasopressor and Sedative Agents on Cerebrovascular Reactivity and Compensatory Reserve in Traumatic Brain Injury: An Exploratory Analysis.

Neurotrauma Rep 2020 6;1(1):157-168. Epub 2020 Nov 6.

Biomedical Engineering, Faculty of Engineering, University of Manitoba, Winnipeg, Manitoba, Canada.

The impact of vasopressor and sedative drugs on cerebrovascular reactivity in traumatic brain injury (TBI) remains unclear. The aim of this study was to evaluate the impact of changes of doses of commonly administered sedation (i.e., propofol, fentanyl, and ketamine) and vasopressor agents (i.e., norepinephrine [NE], phenylephrine [PE], and vasopressin[VSP]) on cerebrovascular reactivity and compensatory reserve in patients with moderate/severe TBI. Using the Winnipeg Acute TBI Database, we identified 38 patients with more than 1000 distinct changes of infusion rates and more than 500 h of paired drug infusion/physiology data. Cerebrovascular reactivity was assessed using pressure reactivity index (PRx) and cerebral compensatory reserve was assessed using RAP (the correlation [R] between pulse amplitude of intracranial pressure [ICP; A] and ICP [P]). We evaluated the data in two phases. First, we assessed the relationship between mean hourly dose of medication and its relation to both mean hourly index values, and time spent above a given index threshold. Second, we evaluated time-series data for each individual dose change per medication, assessing for a statistically significant change in PRx and RAP metrics. The results of the analysis confirmed that, overall, the mean hourly dose of sedative (propofol, fentanyl, and ketamine) and vasopressor (NE, PE, and VSP) agents does not impact hourly cerebrovascular reactivity or compensatory reserve measures. Similarly, incremental dose changes in these medications in general do not lead to significant changes in cerebrovascular reactivity or compensatory reserve. For propofol with incremental dose increases, in situations where PRx is intact (i.e., PRx <0 prior), a statistically significant increase in PRx was seen. However, this may not indicate deteriorating cerebrovascular reactivity as the final PRx (∼0.05) may still be considered to be intact cerebrovascular reactivity. As such, this finding with regards to propofol remains "weak." This study indicates that commonly administered sedative and vasopressor agents with incremental dosing changes have no clinically significant influence on cerebrovascular reactivity or compensatory reserve in TBI. These results should be considered preliminary, requiring further investigation.
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http://dx.doi.org/10.1089/neur.2020.0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703494PMC
November 2020

Cerebrovascular Response to Propofol, Fentanyl, and Midazolam in Moderate/Severe Traumatic Brain Injury: A Scoping Systematic Review of the Human and Animal Literature.

Neurotrauma Rep 2020 13;1(1):100-112. Epub 2020 Oct 13.

Biomedical Engineering, Faculty of Engineering, University of Manitoba, Winnipeg, Manitoba, Canada.

Intravenous propofol, fentanyl, and midazolam are utilized commonly in critical care for metabolic suppression and anesthesia. The impact of propofol, fentanyl, and midazolam on cerebrovasculature and cerebral blood flow (CBF) is unclear in traumatic brain injury (TBI) and may carry important implications, as care is shifting to focus on cerebrovascular reactivity monitoring/directed therapies. The aim of this study was to perform a scoping review of the literature on the cerebrovascular/CBF effects of propofol, fentanyl, and midazolam in human patients with moderate/severe TBI and animal models with TBI. A search of MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and the Cochrane Library from inception to May 2020 was performed. All articles were included pertaining to the administration of propofol, fentanyl, and midazolam, in which the impact on CBF/cerebral vasculature was recorded. We identified 14 studies: 8 that evaluated propofol, 5 that evaluated fentanyl, and 2 that evaluated midazolam. All studies suffered from significant limitations, including: small sample size, and heterogeneous design and measurement techniques. In general, there was no significant change seen in CBF/cerebrovascular response to administration of propofol, fentanyl, or midazolam during experiments where PCO and mean arterial pressure (MAP) were controlled. This review highlights the current knowledge gap surrounding the impact of commonly utilized sedative drugs in TBI care. This work supports the need for dedicated studies, both experimental and human-based, evaluating the impact of these drugs on CBF and cerebrovascular reactivity/response in TBI.
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http://dx.doi.org/10.1089/neur.2020.0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685293PMC
October 2020

Systemic Markers of Injury and Injury Response Are Not Associated with Impaired Cerebrovascular Reactivity in Adult Traumatic Brain Injury: A Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study.

J Neurotrauma 2021 Apr 14;38(7):870-878. Epub 2020 Dec 14.

Division of Anesthesia, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.

The role of extra-cranial injury burden and systemic injury response on cerebrovascular response in traumatic brain injury (TBI) is poorly documented. This study preliminarily assesses the association between admission features of extra-cranial injury burden on cerebrovascular reactivity. Using the Collaborative European Neurotrauma Effectiveness Research in TBI High-Resolution ICU (HR ICU) sub-study cohort, we evaluated those patients with both archived high-frequency digital intra-parenchymal intra-cranial pressure monitoring data of a minimum of 6 h in duration, and the presence of a digital copy of their admission computed tomography (CT) scan. Digital physiologic signals were processed for pressure reactivity index (PRx) and both the percent time above defined PRx thresholds and mean hourly dose above threshold. This was conducted for both the first 72 h and entire duration of recording. Admission extra-cranial injury characteristics and CT injury scores were obtained from the database, with quantitative contusion, edema, intraventricular hemorrhage, and extra-axial lesion volumes were obtained via semi-automated segmentation. Comparison between admission extra-cranial markers of injury and PRx metrics was conducted using Mann-Whitney U testing, and logistic regression techniques, adjusting for known CT injury metrics associated with impaired PRx. A total of 165 patients were included. Evaluating the entire ICU recording period, there was limited association between metrics of extra-cranial injury burden and impaired cerebrovascular reactivity. Using the first 72 h of recording, admission temperature ( = 0.042) and white blood cell % (WBC %;  = 0.013) were statistically associated with impaired cerebrovascular reactivity on Mann-Whitney U and univariate logistic regression. After adjustment for admission age, pupillary status, GCS motor score, pre-hospital hypoxia/hypotension, and intra-cranial CT characteristics associated with impaired reactivity, temperature ( = 0.021) and WBC % ( = 0.013) remained significantly associated with mean PRx values above +0.25 and +0.35, respectively. Markers of extra-cranial injury burden and systemic injury response do not appear to be strongly associated with impaired cerebrovascular reactivity in TBI during both the initial and entire ICU stay.
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http://dx.doi.org/10.1089/neu.2020.7304DOI Listing
April 2021

The cerebrovascular response to norepinephrine: A scoping systematic review of the animal and human literature.

Pharmacol Res Perspect 2020 10;8(5):e00655

Biomedical Engineering, Faculty of Engineering, University of Manitoba, Winnipeg, Canada.

Intravenous norepinephrine (NE) is utilized commonly in critical care for cardiovascular support. NE's impact on cerebrovasculature is unclear and may carry important implications during states of critical neurological illness. The aim of the study was to perform a scoping review of the literature on the cerebrovascular/cerebral blood flow (CBF) effects of NE. A search of MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to December 2019 was performed. All manuscripts pertaining to the administration of NE, in which the impact on CBF/cerebral vasculature was recorded, were included. We identified 62 animal studies and 26 human studies. Overall, there was a trend to a direct vasoconstriction effect of NE on the cerebral vasculature, with conflicting studies having demonstrated both increases and decreases in regional CBF (rCBF) or global CBF. Healthy animals and those undergoing cardiopulmonary resuscitation demonstrated a dose-dependent increase in CBF with NE administration. However, animal models and human patients with acquired brain injury had varied responses in CBF to NE administration. The animal models indicate an increase in cerebral vasoconstriction with NE administration through the alpha receptors in vessels. Global and rCBF during the injection of NE displays a wide variation depending on treatment and model/patient.
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http://dx.doi.org/10.1002/prp2.655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510331PMC
October 2020

The impact of hypertonic saline on cerebrovascular reactivity and compensatory reserve in traumatic brain injury: an exploratory analysis.

Acta Neurochir (Wien) 2020 11 21;162(11):2683-2693. Epub 2020 Sep 21.

Biomedical Engineering, Faculty of Engineering, University of Manitoba, Winnipeg, Canada.

Background: Intravenous hypertonic saline is utilized commonly in critical care for treatment of acute or refractory elevations of intracranial pressure (ICP) in traumatic brain injury (TBI) patients. Though there is a clear understanding of the general physiological effects of a hypertonic saline solution over long periods of time, smaller epoch effects of hypertonic saline (HTS) have not been thoroughly analyzed. The aim of this study was to perform a direct evaluation of the high-frequency response of HTS on the cerebrovascular physiological responses in TBI.

Methods: We retrospectively reviewed our prospectively maintained adult TBI database for those with archived high-frequency cerebral physiology and available HTS treatment information. We evaluated different epochs of physiology around HTS bolus dosing, comparing pre- with post-HTS. We assessed for changes in slow fluctuations in ICP, pulse amplitude of ICP (AMP), cerebral perfusion pressure (CPP), mean arterial pressure (MAP), cerebrovascular reactivity (as measured through pressure reactivity index (PRx)), and cerebral compensatory reserve (correlation (R) between AMP (A) and ICP (P)). Comparisons of mean measures and percentage time above clinically relevant thresholds for the physiological parameters were compared pre- and post-HTS using descriptive statistics and Mann-Whitney U testing. We assessed for subgroups of physiological responses using latent profile analysis (LPA).

Results: Fifteen patients underwent 69 distinct bolus infusions of hypertonic saline. Apart from the well-documented decrease in ICP, there was also a reduction in AMP. The analysis of cerebrovascular reactivity response to HTS solution had two main effects. For patients with grossly impaired cerebrovascular reactivity pre-HTS (PRx > + 0.30), HTS bolus led to improved reactivity. However, for those with intact cerebrovascular reactivity pre-HTS (PRx < 0), HTS bolus demonstrated a trend towards more impaired reactivity. This indicates that HTS has different impacts, dependent on pre-bolus cerebrovascular status. There was no significant change in metrics of cerebral compensatory reserve. LPA failed to demonstrate any subgroups of physiological responses to HTS administration.

Conclusions: The direct decrease in ICP and AMP confirms that a bolus dose of a HTS solution is an effective therapeutic agent for intracranial hypertension. However, in patients with intact autoregulation, hypertonic saline may impair cerebral hemodynamics. These findings regarding cerebrovascular reactivity remain preliminary and require further investigation.
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http://dx.doi.org/10.1007/s00701-020-04579-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505542PMC
November 2020

Descriptive analysis of low versus elevated intracranial pressure on cerebral physiology in adult traumatic brain injury: a CENTER-TBI exploratory study.

Acta Neurochir (Wien) 2020 11 4;162(11):2695-2706. Epub 2020 Sep 4.

Brain Physics Lab, Division of Neurosurgery, Dept of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Background: To date, the cerebral physiologic consequences of persistently elevated intracranial pressure (ICP) have been based on either low-resolution physiologic data or retrospective high-frequency data from single centers. The goal of this study was to provide a descriptive multi-center analysis of the cerebral physiologic consequences of ICP, comparing those with normal ICP to those with elevated ICP.

Methods: The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) High-Resolution Intensive Care Unit (HR-ICU) sub-study cohort was utilized. The first 3 days of physiologic recording were analyzed, evaluating and comparing those patients with mean ICP < 15 mmHg versus those with mean ICP > 20 mmHg. Various cerebral physiologic parameters were derived and evaluated, including ICP, brain tissue oxygen (PbtO), cerebral perfusion pressure (CPP), pulse amplitude of ICP (AMP), cerebrovascular reactivity, and cerebral compensatory reserve. The percentage time and dose above/below thresholds were also assessed. Basic descriptive statistics were employed in comparing the two cohorts.

Results: 185 patients were included, with 157 displaying a mean ICP below 15 mmHg and 28 having a mean ICP above 20 mmHg. For admission demographics, only admission Marshall and Rotterdam CT scores were statistically different between groups (p = 0.017 and p = 0.030, respectively). The high ICP group displayed statistically worse CPP, PbtO, cerebrovascular reactivity, and compensatory reserve. The high ICP group displayed worse 6-month mortality (p < 0.0001) and poor outcome (p = 0.014), based on the Extended Glasgow Outcome Score.

Conclusions: Low versus high ICP during the first 72 h after moderate/severe TBI is associated with significant disparities in CPP, AMP, cerebrovascular reactivity, cerebral compensatory reserve, and brain tissue oxygenation metrics. Such ICP extremes appear to be strongly related to 6-month patient outcomes, in keeping with previous literature. This work provides multi-center validation for previously described single-center retrospective results.
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http://dx.doi.org/10.1007/s00701-020-04485-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550280PMC
November 2020

Association between Physiological Signal Complexity and Outcomes in Moderate and Severe Traumatic Brain Injury: A CENTER-TBI Exploratory Analysis of Multi-Scale Entropy.

J Neurotrauma 2021 01 23;38(2):272-282. Epub 2020 Sep 23.

Brain Physics Laboratory, Division of Neurosurgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.

In traumatic brain injury (TBI), preliminary retrospective work on signal entropy suggests an association with global outcome. The goal of this study was to provide multi-center validation of the association between multi-scale entropy (MSE) of cardiovascular and cerebral physiological signals, with six-month outcome. Using the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit (ICU) cohort, we selected patients with a minimum of 72 h of physiological recordings and a documented six-month Glasgow Outcome Scale Extended (GOSE) score. The 10-sec summary data for heart rate (HR), mean arterial pressure (MAP), intracranial pressure (ICP), and pulse amplitude of ICP (AMP) were derived across the first 72 h of data. The MSE complexity index (MSE-Ci) was determined for HR, MAP, ICP, and AMP, with the association between MSE and dichotomized six-month outcomes assessed using Mann-Whitney testing and logistic regression analysis. A total of 160 patients had a minimum of 72 h of recording and a documented outcome. Decreased HR MSE-Ci (7.3 [interquartile range (IQR) 5.4 to 10.2] vs. 5.1 [IQR 3.1 to 7.0];  = 0.002), lower ICP MSE-Ci (11.2 [IQR 7.5 to 14.2] vs. 7.3 [IQR 6.1 to 11.0];  = 0.009), and lower AMP MSE-Ci (10.9 [IQR 8.0 to 13.7] vs. 8.7 [IQR 6.6 to 11.0];  = 0.022), were associated with death. Similarly, lower HR MSE-Ci (8.0 [IQR 6.2 to 10.9] vs. 6.2 [IQR 3.9 to 8.7];  = 0.003) and lower ICP MSE-Ci (11.4 [IQR 8.6 to 14.4)] vs. 9.2 [IQR 6.0 to 13.5]), were associated with unfavorable outcome. Logistic regression analysis confirmed that lower HR MSE-Ci and ICP MSE-Ci were associated with death and unfavorable outcome at six months. These findings suggest that a reduction in cardiovascular and cerebrovascular system entropy is associated with worse outcomes. Further work in the field of signal complexity in TBI multi-modal monitoring is required.
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http://dx.doi.org/10.1089/neu.2020.7249DOI Listing
January 2021

Dural Venous Sinus Thrombosis in Patients Presenting with Blunt Traumatic Brain Injuries and Skull Fractures: A Systematic Review and Meta-Analysis.

World Neurosurg 2020 10 29;142:495-505.e3. Epub 2020 Jun 29.

Division of Neurosurgery, Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address:

Background: Dural venous sinus thrombosis (DVST) is an increasingly recognized complication of blunt traumatic brain injury (TBI) and skull fractures. However, data concerning epidemiology and clinical significance of DVST are unclear. Determining the disease burden in patients with TBI is an important first step to guide future studies assessing the natural course of traumatic DVST or the effects of its treatment. Therefore, we performed to our knowledge the first systematic review and meta-analysis evaluating the prevalence of DVST in patients with TBI and skull fractures.

Methods: MEDLINE and Embase databases were systematically searched for relevant studies published up to March 2018. All studies that assessed the prevalence of DVST among patients with TBI who underwent a vascular imaging study were included. The primary outcome was the presence or absence of DVST on imaging. A random-effects meta-analysis was used to pool studies.

Results: Our systematic review yielded 638 articles, and 13 articles met inclusion criteria. In patients with skull fractures adjacent to a venous sinus, the prevalence was 26.2% (95% confidence interval = 19.4%-34.4%). This elevated risk was similar between adult (pooled estimate 23.8%; 95% CI = 16.2%-33.5%) and pediatric (pooled estimate 31.3%; 95% CI = 19.1%-46.9%) populations.

Conclusions: We found an unexpectedly high and consistent frequency of DVST among patients with skull fractures regardless of age group or severity of brain injury. These findings are important and highlight the need for further understanding the natural history of DVST and providing better guidelines on its management.
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http://dx.doi.org/10.1016/j.wneu.2020.06.117DOI Listing
October 2020

Analysis of Normal High-Frequency Intracranial Pressure Values and Treatment Threshold in Neurocritical Care Patients: Insights into Normal Values and a Potential Treatment Threshold.

JAMA Neurol 2020 09;77(9):1150-1158

Brain and Spinal Cord Injury Center (BASIC), University of California, San Francisco.

Importance: Intracranial pressure (ICP) elevation is a compartment syndrome that impairs blood flow to the brain. Despite the importance of ICP values in neurocritical care, normal ICP values and the precise ICP threshold at which treatment should be initiated remain uncertain.

Objective: To refine our understanding of normal ICP values and determine the ICP threshold most strongly associated with outcome.

Design, Setting, And Participants: Prospective observational study (2004-2010), with outcomes determined at hospital discharge. The study included neurocritical care patients from a single level I trauma center, San Francisco General Hospital. Three hundred eighty-three patients had a traumatic brain injury with or without craniectomy; 140 patients had another indication for ICP monitoring. Consecutive patients were studied. Data analyses were completed between March 2015 and December 2019.

Exposures: Five hundred twenty-three ICP-monitored patients.

Main Outcomes And Measures: A computer system prospectively and automatically collected 1-minute physiologic data from patients in the intensive care unit during a 6-year period. Mean ICP was calculated, as was the proportion of ICP values greater than thresholds from 1 to 80 mm Hg in 1-mm Hg increments. The association between these measures and outcome was explored for various epochs up to 30 days from the time of injury. A principal component analysis was used to explore physiologic changes at various ICP thresholds, and elastic net regression was used to identify ICP thresholds most strongly associated with Glasgow Outcome Scale score at discharge.

Results: Of the 523 studied patients, 70.7% of studied patients were men (n = 370) and 72.1% had a traumatic brain injury (n = 377). A total of 4 090 964 1-minute ICP measurements were recorded for the included patients (7.78 years of recordings). Intracranial pressure values of 8 to 9 mm Hg were most commonly recorded and could possibly reflect normal values. The principal component analysis suggested state shifts in the physiome occurred at ICPs greater than 19 mm Hg and 24 mm Hg. Elastic net regression identified an ICP threshold of 19 mm Hg as most robustly associated with outcome when considering all neurocritical care patients, patients with TBI, and patients with TBI who underwent craniectomy. Intracranial pressure values greater than 19 mm Hg were associated with mortality, while lower values were associated with outcome in surviving patients.

Conclusions And Relevance: This study provides insight into what normal ICP values could be. An ICP threshold of 19 mm Hg was robustly associated with outcome in studied patients, although lower ICP values were associated with outcome in surviving patients.
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http://dx.doi.org/10.1001/jamaneurol.2020.1310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296460PMC
September 2020

Awake Craniotomy Under 3-Tesla Intraoperative Magnetic Resonance Imaging: A Retrospective Descriptive Report and Canadian Institutional Experience.

J Neurosurg Anesthesiol 2020 May 29. Epub 2020 May 29.

Department of Surgery, Section-Neurosurgery, Clincian Investigator Program, Max Rady College of Medicine, Rady Faculty of Health Sciences.

Background: The role of high-field 3-Tesla intraoperative magnetic resonance imaging (I-MRI) during awake craniotomy (AC) has not been extensively studied. We report the feasibility and safety of AC during 3-Tesla I-MRI.

Methods: This retrospective descriptive report compared 3 groups: AC with minimal sedation and I-MRI; I-MRI-guided craniotomy under general anesthesia (GA), and; AC without I-MRI. Perioperative factors, surgical, anesthetic and radiologic complications, and postoperative morbidity and mortality were recorded.

Results: Overall, 85 patients are included in this report. Five of 23 patients (22%) who underwent AC with I-MRI had anesthetic complications (nausea/vomiting and conversion to GA) compared with 3 of 40 (8%) who underwent I-MRI-guided craniotomy under GA (nausea/vomiting during extubation, and arrhythmia). Intraoperative surgical complications (seizures and speech deficits) occurred in 5 patients (22%) who underwent AC and I-MRI, excessive intraoperative bleeding occurred in 2 patients (5%) who had I-MRI-guided craniotomy under GA, and 4 of 22 (18%) patients who underwent AC without I-MRI experienced neurological complications (seizures, motor deficits, and transient loss of consciousness). Eight patients (20%) who had I-MRI with GA had postoperative complications, largely neurological. The duration of surgery and anesthesia were shortest in the group of patients receiving AC without I-MRI. Seventy-three percent of the patients in this group had residual tumor postoperatively compared with 44% and 38% in those having I-MRI with AC or GA, respectively. Patients who underwent I-MRI-guided craniotomy with GA had the highest morbidity (8%) at hospital discharge.

Conclusions: Our institutional experience suggests that AC under 3-Tesla I-MRI could be an option for glioma resection, although firm conclusions cannot be drawn given the limited and heterogenous nature of our data. Future multicenter trials comparing anesthetic and imaging modalities for glioma resection are recommended.
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http://dx.doi.org/10.1097/ANA.0000000000000699DOI Listing
May 2020

The Limited Impact of Current Therapeutic Interventions on Cerebrovascular Reactivity in Traumatic Brain Injury: A Narrative Overview.

Neurocrit Care 2021 02;34(1):325-335

Biomedical Engineering, Faculty of Engineering, University of Manitoba, Winnipeg, Canada.

Current intensive care unit (ICU) treatment strategies for traumatic brain injury (TBI) care focus on intracranial pressure (ICP)- and cerebral perfusion pressure (CPP)-directed therapeutics, dictated by guidelines. Impaired cerebrovascular reactivity in moderate/severe TBI is emerging as a major associate with poor outcome and appears to dominate the landscape of physiologic derangement over the course of a patient's ICU stay. Within this article, we review the literature on the known drivers of impaired cerebrovascular reactivity in adult TBI, highlight the current knowledge surrounding the impact of guideline treatment strategies on continuously monitored cerebrovascular reactivity, and discuss current treatment paradigms for impaired reactivity. Finally, we touch on the areas of future research, as we strive to develop specific therapeutics for impaired cerebrovascular reactivity in TBI. There exists limited literature to suggest advanced age, intracranial injury patterns of diffuse injury, and sustained ICP elevations may drive impaired cerebrovascular reactivity. To date, the literature suggests there is a limited impact of such ICP/CPP guideline-based therapies on cerebrovascular reactivity, with large portions of a given patients ICU period spent with impaired cerebrovascular reactivity. Emerging treatment paradigms focus on the targeting individualized CPP and ICP thresholds based on cerebrovascular reactivity, without directly targeting the pathways involved in its dysfunction. Further work involved in uncovering the molecular pathways involved in impaired cerebrovascular reactivity is required, so that we can develop therapeutics directed at its prevention and treatment.
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http://dx.doi.org/10.1007/s12028-020-01003-4DOI Listing
February 2021
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