Publications by authors named "Manuel Cabeleira"

35 Publications

Python-Embedded Plugin Implementation in ICM+: Novel Tools for Neuromonitoring Time Series Analysis with Examples Using CENTER-TBI Datasets.

Acta Neurochir Suppl 2021 ;131:255-260

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

With the appearance of publicly available, high-resolution, physiological datasets in neurocritical care, like Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI), there is a growing need for tools that could be used by clinical researchers to interrogate this information-rich data. The ICM+ software is widely used for processing data acquired from bedside monitors. Considering the growing popularity of scripting simple-syntax programming languages like Python, particularly among clinical researchers, we have developed an interface in ICM+ that provides a streamlined way of adding Python scripting functionality to the ICM+ calculation engine. The new interface imposes certain requirements on the scripts and needs an accompanying descriptor file that tells ICM+ about the functions implemented, so that they become available to the end user in the same way as native ICM+ functions. ICM+ also now includes a tool that eases the creation of Python functions to be imported. The Python extension works very efficiently, and any user with some degree of experience in scripting can use it to enrich capabilities of ICM+. Depending on the data analysed and calculations performed, Python functions are 15-60% slower than built-in ICM+ functions, which is a more-than-acceptable trade-off for empowering ICM+ with the unlimited analytical freedom offered by extensive Python libraries.
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http://dx.doi.org/10.1007/978-3-030-59436-7_48DOI Listing
June 2021

DeepClean: Self-Supervised Artefact Rejection for Intensive Care Waveform Data Using Deep Generative Learning.

Acta Neurochir Suppl 2021 ;131:235-241

Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, UK.

Waveform physiological data are important in the treatment of critically ill patients in the intensive care unit. Such recordings are susceptible to artefacts, which must be removed before the data can be reused for alerting or reprocessed for other clinical or research purposes. Accurate removal of artefacts reduces bias and uncertainty in clinical assessment, as well as the false positive rate of ICU alarms, and is therefore a key component in providing optimal clinical care. In this work, we present DeepClean, a prototype self-supervised artefact detection system using a convolutional variational autoencoder deep neural network that avoids costly and painstaking manual annotation, requiring only easily obtained 'good' data for training. For a test case with invasive arterial blood pressure, we demonstrate that our algorithm can detect the presence of an artefact within a 10s sample of data with sensitivity and specificity around 90%. Furthermore, DeepClean was able to identify regions of artefacts within such samples with high accuracy, and we show that it significantly outperforms a baseline principal component analysis approach in both signal reconstruction and artefact detection. DeepClean learns a generative model and therefore may also be used for imputation of missing data.
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http://dx.doi.org/10.1007/978-3-030-59436-7_45DOI Listing
June 2021

Automatic Pulse Classification for Artefact Removal Using SAX Strings, a CENTER-TBI Study.

Acta Neurochir Suppl 2021 ;131:231-234

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

High-resolution, waveform-level data from bedside monitors carry important information about a patient's physiology but is also polluted with artefactual data. Manual mark-up is the standard practice for detecting and eliminating artefacts, but it is time-consuming, prone to errors, biased and not suitable for real-time processing.In this paper we present a novel automatic artefact detection technique based on a Symbolic Aggregate approXimation (SAX) technique which makes it possible to represent individual pulses as 'words'. It does that by coding each pulse with a specified number of letters (here six) from a predefined alphabet of characters (here six). The word is then fed to a support vector machine (SVM) and classified as artefactual or physiological.To define the universe of acceptable pulses, the arterial blood pressure from 50 patients was analysed, and acceptable pulses were manually chosen by looking at the average pulse that each 'word' generated. This was then used to train a SVM classifier. To test this algorithm, a dataset with a balanced ratio of clean and artefactual pulses was built, classified and independently evaluated by two observers achieving a sensitivity of 0.972 and 0.954 and a specificity of 0.837 and 0.837 respectively.
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http://dx.doi.org/10.1007/978-3-030-59436-7_44DOI 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

An Update on the COGiTATE Phase II Study: Feasibility and Safety of Targeting an Optimal Cerebral Perfusion Pressure as a Patient-Tailored Therapy in Severe Traumatic Brain Injury.

Acta Neurochir Suppl 2021 ;131:143-147

Department of Intensive Care Medicine, University of Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.

Introduction: Monitoring of cerebral autoregulation (CA) in patients with a traumatic brain injury (TBI) can provide an individual 'optimal' cerebral perfusion pressure (CPP) target (CPPopt) at which CA is best preserved. This potentially offers an individualized precision medicine approach. Retrospective data suggest that deviation of CPP from CPPopt is associated with poor outcomes. We are prospectively assessing the feasibility and safety of this approach in the COGiTATE [CPPopt Guided Therapy: Assessment of Target Effectiveness] study. Its primary objective is to demonstrate the feasibility of individualizing CPP at CPPopt in TBI patients. The secondary objectives are to investigate the safety and physiological effects of this strategy.

Methods: The COGiTATE study has included patients in four European hospitals in Cambridge, Leuven, Nijmegen, and Maastricht (coordinating centre). Patients with severe TBI requiring intracranial pressure (ICP)-directed therapy are allocated into one of two groups. In the intervention group, CPPopt is calculated using a published (modified) algorithm. In the control group, the CPP target recommended in the Brain Trauma Foundation guidelines (CPP 60-70 mmHg) is used.

Results: Patient recruitment started in February 2018 and will continue until 60 patients have been studied. Fifty-one patients (85% of the intended total) have been recruited in October 2019. The first results are expected early 2021.

Conclusion: This prospective evaluation of the feasibility, safety and physiological implications of autoregulation-guided CPP management is providing evidence that will be useful in the design of a future phase III study in severe TBI patients.
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http://dx.doi.org/10.1007/978-3-030-59436-7_29DOI Listing
June 2021

Errors and Consequences of Inaccurate Estimation of Mean Blood Flow Velocity in Cerebral Arteries.

Acta Neurochir Suppl 2021 ;131:23-25

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

Many transcranial Doppler ultrasonography devices estimate the mean flow velocity (FVm) by using the traditional formula (FVsystolic + 2 × FVdiastolic)/3 instead of a more accurate formula calculating it as the time integral of the current flow velocities divided by the integration period. We retrospectively analyzed flow velocity and intracranial pressure signals containing plateau waves (transient intracranial hypertension), which were collected from 14 patients with a traumatic brain injury. The differences in FVm and its derivative pulsatility index (PI) calculated with the two different methods were determined. We found that during plateau waves, when the intracranial pressure (ICP) rose, the error in FVm and PI increased significantly from the baseline to the plateau (from 4.6 ± 2.4 to 9.8 ± 4.9 cm/s, P < 0.05). Similarly, the error in PI also increased during plateau waves (from 0.11 ± 0.07 to 0.44 ± 0.24, P < 0.005). These effects were most likely due to changes in the pulse waveform during increased ICP, which alter the relationship between systolic, diastolic, and mean flow velocities. If a change in the mean ICP is expected, then calculation of FVm with the traditional formula is not recommended.
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http://dx.doi.org/10.1007/978-3-030-59436-7_5DOI Listing
June 2021

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

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

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

Assessment of cerebral autoregulation indices - a modelling perspective.

Sci Rep 2020 06 15;10(1):9600. Epub 2020 Jun 15.

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

Various methodologies to assess cerebral autoregulation (CA) have been developed, including model - based methods (e.g. autoregulation index, ARI), correlation coefficient - based methods (e.g. mean flow index, Mx), and frequency domain - based methods (e.g. transfer function analysis, TF). Our understanding of relationships among CA indices remains limited, partly due to disagreement of different studies by using real physiological signals, which introduce confounding factors. The influence of exogenous noise on CA parameters needs further investigation. Using a set of artificial cerebral blood flow velocities (CBFV) generated from a well-known CA model, this study aims to cross-validate the relationship among CA indices in a more controlled environment. Real arterial blood pressure (ABP) measurements from 34 traumatic brain injury patients were applied to create artificial CBFVs. Each ABP recording was used to create 10 CBFVs corresponding to 10 CA levels (ARI from 0 to 9). Mx, TF phase, gain and coherence in low frequency (LF) and very low frequency (VLF) were calculated. The influence of exogenous noise was investigated by adding three levels of colored noise to the artificial CBFVs. The result showed a significant negative relationship between Mx and ARI (r = -0.95, p < 0.001), and it became almost purely linear when ARI is between 3 to 6. For transfer function parameters, ARI positively related with phase (r = 0.99 at VLF and 0.93 at LF, p < 0.001) and negatively related with gain_VLF(r = -0.98, p < 0.001). Exogenous noise changed the actual values of the CA parameters and increased the standard deviation. Our results show that different methods can lead to poor correlation between some of the autoregulation parameters even under well controlled situations, undisturbed by unknown confounding factors. They also highlighted the importance of exogenous noise, showing that even the same CA value might correspond to different CA levels under different 'noise' conditions.
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http://dx.doi.org/10.1038/s41598-020-66346-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295753PMC
June 2020

Evaluation of the relationship between slow-waves of intracranial pressure, mean arterial pressure and brain tissue oxygen in TBI: a CENTER-TBI exploratory analysis.

J Clin Monit Comput 2021 Aug 16;35(4):711-722. Epub 2020 May 16.

Division of Anaesthesia, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Brain tissue oxygen (PbtO) monitoring in traumatic brain injury (TBI) has demonstrated strong associations with global outcome. Additionally, PbtO signals have been used to derive indices thought to be associated with cerebrovascular reactivity in TBI. However, their true relationship to slow-wave vasogenic fluctuations associated with cerebral autoregulation remains unclear. The goal of this study was to investigate the relationship between slow-wave fluctuations of intracranial pressure (ICP), mean arterial pressure (MAP) and PbtO over time. Using the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) high resolution ICU sub-study cohort, we evaluated those patients with recorded high-frequency digital intra-parenchymal ICP and PbtO monitoring data of a minimum of 6 h in duration. Digital physiologic signals were processed for ICP, MAP, and PbtO slow-waves using a moving average filter to decimate the high-frequency signal. The first 5 days of recording were analyzed. The relationship between ICP, MAP and PbtO slow-waves over time were assessed using autoregressive integrative moving average (ARIMA) and vector autoregressive integrative moving average (VARIMA) modelling, as well as Granger causality testing. A total of 47 patients were included. The ARIMA structure of ICP and MAP were similar in time, where PbtO displayed different optimal structure. VARIMA modelling and IRF plots confirmed the strong directional relationship between MAP and ICP, demonstrating an ICP response to MAP impulse. PbtO slow-waves, however, failed to demonstrate a definite response to ICP and MAP slow-wave impulses. These results raise questions as to the utility of PbtO in the derivation of cerebrovascular reactivity measures in TBI. There is a reproducible relationship between slow-wave fluctuations of ICP and MAP, as demonstrated across various time-series analytic techniques. PbtO does not appear to reliably respond in time to slow-wave fluctuations in MAP, as demonstrated on various VARIMA models across all patients. These findings suggest that PbtO should not be utilized in the derivation of cerebrovascular reactivity metrics in TBI, as it does not appear to be responsive to changes in MAP in the slow-waves. These findings corroborate previous results regarding PbtO based cerebrovascular reactivity indices.
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http://dx.doi.org/10.1007/s10877-020-00527-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286934PMC
August 2021

Brain Tissue Oxygen and Cerebrovascular Reactivity in Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Exploratory Analysis of Insult Burden.

J Neurotrauma 2020 09 4;37(17):1854-1863. Epub 2020 May 4.

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

Pressure reactivity index (PRx) and brain tissue oxygen (PbtO) are associated with outcome in traumatic brain injury (TBI). This study explores the relationship between PRx and PbtO in adult moderate/severe TBI. Using the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) high resolution intensive care unit (ICU) sub-study cohort, we evaluated those patients with archived high-frequency digital intraparenchymal intracranial pressure (ICP) and PbtO monitoring data of, a minimum of 6 h in duration, and the presence of a 6 month Glasgow Outcome Scale -Extended (GOSE) score. Digital physiological signals were processed for ICP, PbtO, and PRx, with the % time above/below defined thresholds determined. The duration of ICP, PbtO, and PRx derangements was characterized. Associations with dichotomized 6-month GOSE (alive/dead, and favorable/unfavorable outcome; ≤ 4 = unfavorable), were assessed. A total of 43 patients were included. Severely impaired cerebrovascular reactivity was seen during elevated ICP and low PbtO episodes. However, most of the acute ICU physiological derangements were impaired cerebrovascular reactivity, not ICP elevations or low PbtO episodes. Low PbtO without PRx impairment was rarely seen. % time spent above PRx threshold was associated with mortality at 6 months for thresholds of 0 (area under the curve [AUC] 0.734,  = 0.003), > +0.25 (AUC 0.747,  = 0.002) and > +0.35 (AUC 0.745,  = 0.002). Similar relationships were not seen for % time with ICP >20 mm Hg, and PbtO < 20 mm Hg in this cohort. Extreme impairment in cerebrovascular reactivity is seen during concurrent episodes of elevated ICP and low PbtO. However, the majority of the deranged cerebral physiology seen during the acute ICU phase is impairment in cerebrovascular reactivity, with most impairment occurring in the presence of normal PbtO levels. Measures of cerebrovascular reactivity appear to display the most consistent associations with global outcome in TBI, compared with ICP and PbtO.
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http://dx.doi.org/10.1089/neu.2020.7024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484893PMC
September 2020

Diffuse Intracranial Injury Patterns Are Associated with Impaired Cerebrovascular Reactivity in Adult Traumatic Brain Injury: A CENTER-TBI Validation Study.

J Neurotrauma 2020 07 6;37(14):1597-1608. Epub 2020 Apr 6.

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

Recent single-center retrospective analysis displayed the association between admission computed tomography (CT) markers of diffuse intracranial injury and worse cerebrovascular reactivity. The goal of this study was to further explore these associations using the prospective multi-center Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) high-resolution intensive care unit (HR ICU) data set. Using the CENTER-TBI HR ICU sub-study cohort, we evaluated those patients with both archived high-frequency digital physiology (100 Hz or higher) and the presence of a digital admission CT scan. Physiological signals were processed for pressure reactivity index (PRx) and both the percent (%) time above defined PRx thresholds and mean hourly dose above threshold. Admission CT injury scores were obtained from the database. Quantitative contusion, edema, intraventricular hemorrhage (IVH), and extra-axial lesion volumes were obtained via semi-automated segmentation. Comparison between admission CT characteristics and PRx metrics was conducted using Mann-U, Jonckheere-Terpstra testing, with a combination of univariate linear and logistic regression techniques. A total of 165 patients were included. Cisternal compression and high admission Rotterdam and Helsinki CT scores, and Marshall CT diffuse injury sub-scores were associated with increased percent (%) time and hourly dose above PRx threshold of 0, +0.25, and +0.35 ( < 0.02 for all). Logistic regression analysis displayed an association between deep peri-contusional edema and mean PRx above a threshold of +0.25. These results suggest that diffuse injury patterns, consistent with acceleration/deceleration forces, are associated with impaired cerebrovascular reactivity. Diffuse admission intracranial injury patterns appear to be consistently associated with impaired cerebrovascular reactivity, as measured through PRx. This is in keeping with the previous single-center retrospective literature on the topic. This study provides multi-center validation for those results, and provides preliminary data to support potential risk stratification for impaired cerebrovascular reactivity based on injury pattern.
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http://dx.doi.org/10.1089/neu.2019.6959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336886PMC
July 2020

Statistical Cerebrovascular Reactivity Signal Properties after Secondary Decompressive Craniectomy in Traumatic Brain Injury: A CENTER-TBI Pilot Analysis.

J Neurotrauma 2020 06 25;37(11):1306-1314. Epub 2020 Feb 25.

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

Decompressive craniectomy (DC) in traumatic brain injury (TBI) has been suggested to influence cerebrovascular reactivity. We aimed to determine if the statistical properties of vascular reactivity metrics and slow-wave relationships were impacted after DC, as such information would allow us to comment on whether vascular reactivity monitoring remains reliable after craniectomy. Using the CENTER-TBI High Resolution Intensive Care Unit (ICU) Sub-Study cohort, we selected those secondary DC patients with high-frequency physiological data for both at least 24 h pre-DC, and more than 48 h post-DC. Data for all physiology measures were separated into the 24 h pre-DC, the first 48 h post-DC, and beyond 48 h post-DC. We produced slow-wave data sheets for intracranial pressure (ICP) and mean arterial pressure (MAP) per patient. We also derived a Pressure Reactivity Index (PRx) as a continuous cerebrovascular reactivity metric updated every minute. The time-series behavior of the PRx was modeled for each time period per patient. Finally, the relationship between ICP and MAP during these three time periods was assessed using time-series vector autoregressive integrative moving average (VARIMA) models, impulse response function (IRF) plots, and Granger causality testing. Ten patients were included in this study. Mean PRx and proportion of time above PRx thresholds were not affected by craniectomy. Similarly, PRx time-series structure was not affected by DC, when assessed in each individual patient. This was confirmed with Granger causality testing, and VARIMA IRF plotting for the MAP/ICP slow-wave relationship. PRx metrics and statistical time-series behavior appear not to be substantially influenced by DC. Similarly, there is little change in the relationship between slow waves of ICP and MAP before and after DC. This may suggest that cerebrovascular reactivity monitoring in the setting of DC may still provide valuable information regarding autoregulation.
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http://dx.doi.org/10.1089/neu.2019.6726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249464PMC
June 2020

Association between Cerebrovascular Reactivity Monitoring and Mortality Is Preserved When Adjusting for Baseline Admission Characteristics in Adult Traumatic Brain Injury: A CENTER-TBI Study.

J Neurotrauma 2020 05 30;37(10):1233-1241. Epub 2019 Dec 30.

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

Cerebral autoregulation, as measured using the pressure reactivity index (PRx), has been related to global patient outcome in adult patients with traumatic brain injury (TBI). To date, this has been documented without accounting for standard baseline admission characteristics and intracranial pressure (ICP). We evaluated this association, adjusting for baseline admission characteristics and ICP, in a multi-center, prospective cohort. We derived PRx as the correlation between ICP and mean arterial pressure in prospectively collected multi-center data from the High-Resolution Intensive Care Unit (ICU) cohort of the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. Multi-variable logistic regression models were analyzed to assess the association between global outcome (measured as either mortality or dichotomized Glasgow Outcome Score-Extended [GOSE]) and a range of covariates (IMPACT [International Mission for Prognosis and Analysis of Clinical Trials] Core and computed tomography [CT] variables, ICP, and PRx). Performance of these models in outcome association was compared using area under the receiver operating curve (AUC) and Nagelkerke's pseudo-R. One hundred ninety-three patients had a complete data set for analysis. The addition of percent time above threshold for PRx improved AUC and displayed statistically significant increases in Nagelkerke's pseudo-R over the IMPACT Core and IMPACT Core + CT models for mortality. The addition of PRx monitoring to IMPACT Core ± CT + ICP models accounted for additional variance in mortality, when compared to models with IMPACT Core ± CT + ICP alone. The addition of cerebrovascular reactivity monitoring, through PRx, provides a statistically significant increase in association with mortality at 6 months. Our data suggest that cerebrovascular reactivity monitoring may provide complementary information regarding outcomes in TBI.
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http://dx.doi.org/10.1089/neu.2019.6808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232651PMC
May 2020

Feasibility of individualised severe traumatic brain injury management using an automated assessment of optimal cerebral perfusion pressure: the COGiTATE phase II study protocol.

BMJ Open 2019 09 20;9(9):e030727. Epub 2019 Sep 20.

Division of Anaesthesia, University of Cambridge, Cambridge, UK.

Introduction: Individualising therapy is an important challenge for intensive care of patients with severe traumatic brain injury (TBI). Targeting a cerebral perfusion pressure (CPP) tailored to optimise cerebrovascular autoregulation has been suggested as an attractive strategy on the basis of a large body of retrospective observational data. The objective of this study is to prospectively assess the feasibility and safety of such a strategy compared with fixed thresholds which is the current standard of care from international consensus guidelines.

Methods And Analysis: CPPOpt Guided Therapy: Assessment of Target Effectiveness (COGiTATE) is a prospective, multicentre, non-blinded randomised, controlled trial coordinated from Maastricht University Medical Center, Maastricht (The Netherlands). The other original participating centres are Cambridge University NHS Foundation Trust, Cambridge (UK), and University Hospitals Leuven, Leuven (Belgium). Adult severe TBI patients requiring intracranial pressure monitoring are randomised within the first 24 hours of admission in neurocritical care unit. For the control arm, the CPP target is the Brain Trauma Foundation guidelines target (60-70 mm Hg); for the intervention group an automated CPP target is provided as the CPP at which the patient's cerebrovascular reactivity is best preserved (CPPopt). For a maximum of 5 days, attending clinicians review the CPP target 4-hourly. The main hypothesis of COGiTATE are: (1) in the intervention group the percentage of the monitored time with measured CPP within a range of 5 mm Hg above or below CPPopt will reach 36%; (2) the difference in between groups in daily therapy intensity level score will be lower or equal to 3.

Ethics And Dissemination: Ethical approval has been obtained for each participating centre. The results will be presented at international scientific conferences and in peer-reviewed journals.

Trial Registration Number: NCT02982122.
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http://dx.doi.org/10.1136/bmjopen-2019-030727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756360PMC
September 2019

Cerebrovascular reactivity is not associated with therapeutic intensity in adult traumatic brain injury: a CENTER-TBI analysis.

Acta Neurochir (Wien) 2019 09 25;161(9):1955-1964. Epub 2019 Jun 25.

Division of Anaesthesia, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Background: Impaired cerebrovascular reactivity in adult traumatic brain injury (TBI) is known to be associated with poor outcome. However, there has yet to be an analysis of the association between the comprehensively assessed intracranial hypertension therapeutic intensity level (TIL) and cerebrovascular reactivity.

Methods: Using the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit (ICU) cohort, we derived pressure reactivity index (PRx) as the moving correlation coefficient between slow-wave in ICP and mean arterial pressure, updated every minute. Mean daily PRx, and daily % time above PRx of 0 were calculated for the first 7 days of injury and ICU stay. This data was linked with the daily TIL-Intermediate scores, including total and individual treatment sub-scores. Daily mean PRx variable values were compared for each TIL treatment score via mean, standard deviation, and the Mann U test (Bonferroni correction for multiple comparisons). General fixed effects and mixed effects models for total TIL versus PRx were created to display the relation between TIL and cerebrovascular reactivity.

Results: A total of 249 patients with 1230 ICU days of high frequency physiology matched with daily TIL, were assessed. Total TIL was unrelated to daily PRx. Most TIL sub-scores failed to display a significant relationship with the PRx variables. Mild hyperventilation (p < 0.0001), mild hypothermia (p = 0.0001), high levels of sedation for ICP control (p = 0.0001), and use vasopressors for CPP management (p < 0.0001) were found to be associated with only a modest decrease in mean daily PRx or % time with PRx above 0.

Conclusions: Cerebrovascular reactivity remains relatively independent of intracranial hypertension therapeutic intensity, suggesting inadequacy of current TBI therapies in modulating impaired autoregulation. These findings support the need for investigation into the molecular mechanisms involved, or individualized physiologic targets (ICP, CPP, or Co2) in order to treat dysautoregulation actively.
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http://dx.doi.org/10.1007/s00701-019-03980-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704258PMC
September 2019

Patient-specific ICP Epidemiologic Thresholds in Adult Traumatic Brain Injury: A CENTER-TBI Validation Study.

J Neurosurg Anesthesiol 2021 Jan;33(1):28-38

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

Background: Patient-specific epidemiologic intracranial pressure (ICP) thresholds in adult traumatic brain injury (TBI) have emerged, using the relationship between pressure reactivity index (PRx) and ICP, displaying stronger association with outcome over existing guideline thresholds. The goal of this study was to explore this relationship in a multi-center cohort in order to confirm the previous finding.

Methods: Using the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit cohort, we derived individualized epidemiologic ICP thresholds for each patient using the relationship between PRx and ICP. Mean hourly dose of ICP was calculated for every patient for the following thresholds: 20, 22 mm Hg and the patient's individual ICP threshold. Univariate logistic regression models were created comparing mean hourly dose of ICP above thresholds to dichotomized outcome at 6 to 12 months, based on Glasgow Outcome Score-Extended (GOSE) (alive/dead-GOSE≥2/GOSE=1; favorable/unfavorable-GOSE 5 to 8/GOSE 1 to 4, respectively).

Results: Individual thresholds were identified in 65.3% of patients (n=128), in keeping with previous results (23.0±11.8 mm Hg [interquartile range: 14.9 to 29.8 mm Hg]). Mean hourly dose of ICP above individual threshold provides superior discrimination (area under the receiver operating curve [AUC]=0.678, P=0.029) over mean hourly dose above 20 mm Hg (AUC=0.509, P=0.03) or above 22 mm Hg (AUC=0.492, P=0.035) on univariate analysis for alive/dead outcome at 6 to 12 months. The AUC for mean hourly dose above individual threshold trends to higher values for favorable/unfavorable outcome, but fails to reach statistical significance (AUC=0.610, P=0.060). This was maintained when controlling for baseline admission characteristics.

Conclusions: Mean hourly dose of ICP above individual epidemiologic ICP threshold has stronger associations with mortality compared with the dose above Brain Trauma Foundation defined thresholds of 20 or 22 mm Hg, confirming prior findings. Further studies on patient-specific epidemiologic ICP thresholds are required.
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http://dx.doi.org/10.1097/ANA.0000000000000616DOI Listing
January 2021

Compensatory-reserve-weighted intracranial pressure versus intracranial pressure for outcome association in adult traumatic brain injury: a CENTER-TBI validation study.

Acta Neurochir (Wien) 2019 07 3;161(7):1275-1284. Epub 2019 May 3.

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

Background: Compensatory-reserve-weighted intracranial pressure (wICP) has recently been suggested as a supplementary measure of intracranial pressure (ICP) in adult traumatic brain injury (TBI), with a single-center study suggesting an association with mortality at 6 months. No multi-center studies exist to validate this relationship. The goal was to compare wICP to ICP for association with outcome in a multi-center TBI cohort.

Methods: Using the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit (ICU) cohort, we derived ICP and wICP (calculated as wICP = (1 - RAP) × ICP; where RAP is the compensatory reserve index derived from the moving correlation between pulse amplitude of ICP and ICP). Various univariate logistic regression models were created comparing ICP and wICP to dichotomized outcome at 6 to 12 months, based on Glasgow Outcome Score-Extended (GOSE) (alive/dead-GOSE ≥ 2/GOSE = 1; favorable/unfavorable-GOSE 5 to 8/GOSE 1 to 4, respectively). Models were compared using area under the receiver operating curves (AUC) and p values.

Results: wICP displayed higher AUC compared to ICP on univariate regression for alive/dead outcome compared to mean ICP (AUC 0.712, 95% CI 0.615-0.810, p = 0.0002, and AUC 0.642, 95% CI 0.538-746, p < 0.0001, respectively; no significant difference on Delong's test), and for favorable/unfavorable outcome (AUC 0.627, 95% CI 0.548-0.705, p = 0.015, and AUC 0.495, 95% CI 0.413-0.577, p = 0.059; significantly different using Delong's test p = 0.002), with lower wICP values associated with improved outcomes (p < 0.05 for both). These relationships on univariate analysis held true even when comparing the wICP models with those containing both ICP and RAP integrated area under the curve over time (p < 0.05 for all via Delong's test).

Conclusions: Compensatory-reserve-weighted ICP displays superior outcome association for both alive/dead and favorable/unfavorable dichotomized outcomes in adult TBI, through univariate analysis. Lower wICP is associated with better global outcomes. The results of this study provide multi-center validation of those seen in a previous single-center study.
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http://dx.doi.org/10.1007/s00701-019-03915-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581920PMC
July 2019

Correction to: Univariate comparison of performance of different cerebrovascular reactivity indices for outcome association in adult TBI: a CENTER-TBI study.

Acta Neurochir (Wien) 2019 Jun;161(6):1229

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

Incorrect family name of Nino Stocchetti.
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http://dx.doi.org/10.1007/s00701-019-03896-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828283PMC
June 2019

Univariate comparison of performance of different cerebrovascular reactivity indices for outcome association in adult TBI: a CENTER-TBI study.

Acta Neurochir (Wien) 2019 06 15;161(6):1217-1227. Epub 2019 Mar 15.

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

Background: Monitoring cerebrovascular reactivity in adult traumatic brain injury (TBI) has been linked to global patient outcome. Three intra-cranial pressure (ICP)-derived indices have been described. It is unknown which index is superior for outcome association in TBI outside previous single-center evaluations. The goal of this study is to evaluate indices for 6- to 12-month outcome association using uniform data harvested in multiple centers.

Methods: Using the prospectively collected data from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study, the following indices of cerebrovascular reactivity were derived: PRx (correlation between ICP and mean arterial pressure (MAP)), PAx (correlation between pulse amplitude of ICP (AMP) and MAP), and RAC (correlation between AMP and cerebral perfusion pressure (CPP)). Univariate logistic regression models were created to assess the association between vascular reactivity indices with global dichotomized outcome at 6 to 12 months, as assessed by Glasgow Outcome Score-Extended (GOSE). Models were compared via area under the receiver operating curve (AUC) and Delong's test.

Results: Two separate patient groups from this cohort were assessed: the total population with available data (n = 204) and only those without decompressive craniectomy (n = 159), with identical results. PRx, PAx, and RAC perform similar in outcome association for both dichotomized outcomes, alive/dead and favorable/unfavorable, with RAC trending towards higher AUC values. There were statistically higher mean values for the index, % time above threshold, and hourly dose above threshold for each of PRx, PAx, and RAC in those patients with poor outcomes.

Conclusions: PRx, PAx, and RAC appear similar in their associations with 6- to 12-month outcome in moderate/severe adult TBI, with RAC showing tendency to achieve stronger associations. Further work is required to determine the role for each of these cerebrovascular indices in monitoring of TBI patients.
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http://dx.doi.org/10.1007/s00701-019-03844-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525666PMC
June 2019

Optic nerve sheath diameter ultrasonography at admission as a predictor of intracranial hypertension in traumatic brain injured patients: a prospective observational study.

J Neurosurg 2019 Mar 8;132(4):1279-1285. Epub 2019 Mar 8.

3Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.

Objective: Intracranial hypertension and impaired cerebral autoregulation are common causes of secondary injuries in patients with traumatic brain injury (TBI). The primary outcome of this study was to assess whether a noninvasive method to estimate intracranial pressure (ICP) based on the ultrasonography of the optic nerve sheath diameter (ONSD) measured at the time of neurocritical care unit (NCCU) admission is correlated with the mean ICP during NCCU stay. Secondary outcomes were to assess whether ONSD is correlated with the dose of ICP > 20 mm Hg and impaired autoregulation during NCCU stay and with instantaneous ICP and whether ONSD is associated with NCCU mortality.

Methods: This prospective observational monocentric study included adults with severe TBI. ONSD was measured at NCCU admission, immediately after invasive ICP insertion. ONSD-predicted noninvasive ICP (nICPONSD) was calculated according the formula: nICPONSD = 5 × ONSD - 14 (nICPONSD in mm Hg, ONSD in mm). Autoregulation was measured using the pressure reactivity index (PRx).

Results: In total, 100 patients were included in this study. ONSD was significantly correlated with mean ICP (r = 0.46, p < 0.0001), with mean PRx (r = 0.21, p = 0.04), and with the dose of ICP > 20 mm Hg during NCCU stay (r = 0.49, p < 0.0001). Admission nICPONSD was shown to be significantly correlated with instantaneous ICP (r = 0.85, p < 0.001). ONSD at admission was significantly correlated with NCCU mortality (p = 0.02).

Conclusions: ONSD measured at NCCU admission can give important information about patients at risk of developing intracranial hypertension and impaired autoregulation. ONSD examination could be useful to screen patients at admission to determine who would benefit from further invasive ICP monitoring.
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http://dx.doi.org/10.3171/2018.11.JNS182077DOI Listing
March 2019

Comparison of Performance of Different Optimal Cerebral Perfusion Pressure Parameters for Outcome Prediction in Adult Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study.

J Neurotrauma 2019 05 17;36(10):1505-1517. Epub 2018 Dec 17.

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

It has been postulated previously that individualized cerebral perfusion pressure (CPP) targets can be derived from cerebrovascular reactivity indices. Differences between real CPP and target CPP (named generically optimal CPP) has been linked to global outcome in adult traumatic brain injury (TBI). Different vascular reactivity indices can be utilized in the determination. The goal of this study is to evaluate CPPopt parameters, derived from three intracranial pressure (ICP)-derived cerebrovascular reactivity indices, and determine which one is superior for 6- to 12-month outcome prediction. Using the prospectively collected data from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study, the following indices of cerebrovascular reactivity were derived: pressure reactivity index (PRx; correlation between ICP and mean arterial pressure [MAP]), pulse amplitude index (PAx; correlation between pulse amplitude of ICP [AMP] and MAP), and RAC (correlation between AMP and CPP). CPPopt was derived using each index. Univariate logistic regression models were created to assess the association between CPPopt with global dichotomized outcome at 6 to 12 months, as assessed by Glasgow Outcome Score-Extended. Models were compared via area under the receiver operating curve (AUC) and Delong's Test. A total of 204 patients had available data. CPPopt derived from PRx, PAx, and RAC performed variably in their association with outcomes. PRx- and RAC-based CPPopt performed similarly, with RAC parameters trending towards highest AUC values. PAx-based CPPopt parameters failed to reach significant associations with dichotomized outcomes at 6 to 12 months. CPPopt parameters derived from PRx and RAC appear similar in their overall ability for 6- to 12-month outcome prediction in moderate/severe adult TBI.
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http://dx.doi.org/10.1089/neu.2018.6182DOI Listing
May 2019

Impaired cerebral compensatory reserve is associated with admission imaging characteristics of diffuse insult in traumatic brain injury.

Acta Neurochir (Wien) 2018 12 24;160(12):2277-2287. Epub 2018 Sep 24.

Section of Brain Physics, Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.

Background: Continuous assessment of cerebral compensatory reserve is possible using the moving correlation between pulse amplitude of intra-cranial pressure (AMP) and intra-cranial pressure (ICP), called RAP. Little is known about the behavior and associations of this index in adult traumatic brain injury (TBI). The goal of this study is to evaluate the association between admission cerebral imaging findings and RAP over the course of the acute intensive care unit stay.

Methods: We retrospectively reviewed 358 adult TBI patients admitted to the Addenbrooke's Hospital, University of Cambridge, from March 2005 to December 2016. Only non-craniectomy patients were studied. Using archived high frequency physiologic signals, RAP was derived and analyzed over the first 48 h and first 10 days of recording in each patient, using grand mean, percentage of time above various thresholds, and integrated area under the curve (AUC) of RAP over time. Associations between these values and admission computed tomography (CT) injury characteristics were evaluated.

Results: The integrated AUC, based on various thresholds of RAP, was statistically associated with admission CT markers of diffuse TBI and cerebral edema. Admission CT findings of cortical gyral effacement, lateral ventricle compression, diffuse cortical subarachnoid hemorrhage (SAH), thickness of cortical SAH, presence of bilateral contusions, and subcortical diffuse axonal injury (DAI) were all associated with AUC of RAP over time. Joncheere-Terpstra testing indicated a statistically significant increase in mean RAP AUC across ordinal categories of the abovementioned associated CT findings.

Conclusions: RAP is associated with cerebral CT injury patterns of diffuse injury and edema, providing some confirmation of its potential measurement of cerebral compensatory reserve in TBI.
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http://dx.doi.org/10.1007/s00701-018-3681-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267721PMC
December 2018

Wavelet pressure reactivity index: a validation study.

J Physiol 2018 07 13;596(14):2797-2809. Epub 2018 Jun 13.

Baylor College of Medicine, Houston, TX, USA.

Key Points: The brain is vulnerable to damage from too little or too much blood flow. A physiological mechanism termed cerebral autoregulation (CA) exists to maintain stable blood flow even if cerebral perfusion pressure (CPP) is changing. A robust method for assessing CA is not yet available. There are still some problems with the traditional measure, the pressure reactivity index (PRx). We introduce a new method, the wavelet transform method (wPRx), to assess CA using data from two sets of controlled hypotension experiments in piglets: one set had artificially manipulated arterial blood pressure (ABP) oscillations; the other group were spontaneous ABP waves. A significant linear relationship was found between wPRx and PRx in both groups, with wPRx providing a more stable result for the spontaneous waves. Although both methods showed similar accuracy in distinguishing intact and impaired CA, it seems that wPRx tends to perform better than PRx, although not significantly so.

Abstract: We present a novel method to monitor cerebral autoregulation (CA) using the wavelet transform (WT). The new method is validated against the pressure reactivity index (PRx) in two piglet experiments with controlled hypotension. The first experiment (n = 12) had controlled haemorrhage with artificial stationary arterial blood pressure (ABP) and intracranial pressure (ICP) oscillations induced by sinusoidal slow changes in positive end-expiratory pressure ('PEEP group'). The second experiment (n = 17) had venous balloon inflation during spontaneous, non-stationary ABP and ICP oscillations ('non-PEEP group'). The wavelet transform phase shift (WTP) between ABP and ICP was calculated in the frequency range 0.0067-0.05 Hz. Wavelet semblance, the cosine of WTP, was used to make the values comparable to PRx, and the new index was termed wavelet pressure reactivity index (wPRx). The traditional PRx, the running correlation coefficient between ABP and ICP, was calculated. The result showed a significant linear relationship between wPRx and PRx in the PEEP group (R = 0.88) and non-PEEP group (R = 0.56). In the non-PEEP group, wPRx showed better performance than PRx in distinguishing cerebral perfusion pressure (CPP) above and below the lower limit of autoregulation (LLA). When CPP was decreased below LLA, wPRx increased from 0.43 ± 0.28 to 0.69 ± 0.12 (P = 0.003) while PRx increased from 0.07 ± 0.21 to 0.27 ± 0.37 (P = 0.04). Moreover, wPRx provided a more stable result than PRx (SD of PRx was 0.40 ± 0.07, and SD of wPRx was 0.28 ± 0.11, P = 0.001). Assessment of CA using wavelet-derived phase shift between ABP and ICP is feasible.
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http://dx.doi.org/10.1113/JP274708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046066PMC
July 2018

HDF5-Based Data Format for Archiving Complex Neuro-monitoring Data in Traumatic Brain Injury Patients.

Acta Neurochir Suppl 2018 ;126:121-125

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

Objectives: Modern neuro-critical care units generate high volumes of data. These data originate from a multitude of devices in various formats and levels of granularity. We present a new data format intended to store these data in an ordered and homogenous way.

Material And Methods: The adopted data format was based on the hierarchical model, HDF5, which is capable of dealing with a mixture of small and very large datasets with equal ease. It is possible to access and manipulate individual data elements directly within a single file, and this is extensible and versatile.

Results: The file structure that was agreed divided the patient data into four different groups: 'Annotations' for clinical events and sporadic observations, 'Numerics' for all the low-frequency data, 'Waves' for all the high-frequency data and 'Summaries' for the trend data and calculated parameters. The addition of attributes to every group and dataset makes the file self-described. More than 200 files have been successfully collected and stored using this format.

Conclusion: The new file format was implemented in ICM+ software and validated as part of a collaboration with participating centres across Europe.
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http://dx.doi.org/10.1007/978-3-319-65798-1_26DOI Listing
July 2018

Non-invasive Intracranial Pressure Assessment in Brain Injured Patients Using Ultrasound-Based Methods.

Acta Neurochir Suppl 2018 ;126:69-73

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

Background: Non-invasive measurement of intracranial pressure (ICP) can be invaluable in the management of critically ill patients. Invasive measurement of ICP remains the "gold standard" and should be performed when clinical indications are met, but it is invasive and brings some risks. In this project, we aim to validate the non-invasive ICP (nICP) assessment models based on arterious and venous transcranial Doppler ultrasonography (TCD) and optic nerve sheath diameter (ONSD).

Methods: We included brain injured patients requiring invasive ICP monitoring (intraparenchymal or intraventricular). We assessed the concordance between ICP measured non-invasively with arterious [flow velocity diastolic formula (ICP) and pulsatility index (PI)], venous TCD (vPI) and ICP derived from ONSD (nICP) compared to invasive ICP measurement.

Results: Linear regression showed a positive relationship between nICP and ICP for all the methods, except PIv. ICP showed the strongest correlation with invasive ICP (r = 0.61) compared to the other methods (ICP, r = 0.26, p value = 0.0015; PI, r = 0.19, p value = 0.02, vPI, r = 0.056, p value = 0.510). The ability to predict intracranial hypertension was highest for ICP (AUC = 0.91; 95% CI, 0.85-0.97 at ICP > 20 mmHg), with a sensitivity and specificity of 85%, followed by ICP (AUC = 0.67; 95% CI, 0.54-0.79).

Conclusions: Our results demonstrate that among the non-invasive methods studied, ONSD showed the best accuracy in the detection of ICP.
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http://dx.doi.org/10.1007/978-3-319-65798-1_15DOI Listing
July 2018

Computed Tomography Indicators of Deranged Intracranial Physiology in Paediatric Traumatic Brain Injury.

Acta Neurochir Suppl 2018 ;126:29-34

Department of Paediatric Intensive Care, Cambridge University Hospitals, Cambridge, UK.

Objective: Computed tomography (CT) of the brain can allow rapid assessment of intracranial pathology after traumatic brain injury (TBI). Frequently in paediatric TBI, CT imaging can fail to display the classical features of severe brain injury with raised intracranial pressure. The objective of this study was to determine early CT brain features that influence intracranial or systemic physiological trends following paediatric TBI.

Materials And Methods: Thirty-three patients (mean age, 10 years; range, 0.5-16) admitted between 2002 and 2015 were used for the current analysis. Presence of petechial haemorrhages, basal cistern compression, subarachnoid blood, midline shift and extra-axial masses on the initial trauma CT head were assessed. ICP and arterial blood pressure (ABP) were then monitored continuously with an intraparenchymal microtransducer and an indwelling arterial line. Pressure monitors were connected to bedside computers running ICM+ software. Pressure reactivity was determined as the moving correlation between 30, 10-s averages of ABP and ICP (PRx). The mean ICP, ABP, cerebral perfusion pressure (CPP; ABP minus ICP) and PRx were calculated for the whole monitoring period for each patient.

Results: The presence of subarachnoid blood was related to higher ICP, higher ABP and a trend toward higher PRx. Smaller basal cisterns were related to increased ICP (R = -0.42, p = 0.02), impaired PRx (R = -0.5, p = 0.003). The presence of an extra-axial mass was associated with deranged PRx (-0.02 vs. 0.41, p = 0.003) and a trend toward higher ICP (14 vs. 40, p = 0.07). Interestingly the degree of midline shift was not related to ICP or PRx.

Conclusions: The size of the basal cisterns, the presence of subarachnoid blood or an extra-axial mass are all related to disturbed ICP and pressure reactivity in this paediatric TBI cohort. Patients with these features are ideal candidates for invasive multimodal monitoring.
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http://dx.doi.org/10.1007/978-3-319-65798-1_7DOI Listing
July 2018