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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.

The quantification and objective documentation of autonomic dysfunction in traumatic brain injury (TBI) is neither well studied nor extensively validated. Most of the descriptions of autonomic dysfunction in the literature are in the form of vague non-specific clinical manifestations. Few studies propose the use of objective measures of assessing the extent of autonomic dysfunction to link them to the outcome of TBI. Our goal was to perform a scoping systematic review of the literature on the objective documentation of autonomic dysfunction in terms of functional and physiological variables to be linked to outcome of TBI. PubMed/MEDLINE®, BIOSIS, Scopus, Embase, Cochrane Libraries, and Global Health databases were searched. Two reviewers independently screened the results. Full texts for citations passing this initial screen were obtained. Inclusion and exclusion criteria were applied to each article to obtain final articles for review. The initial search yielded 2619 citations. Of 69 articles selected for final review, 14 were chosen based on the inclusion and exclusion criteria and are included in the results of this article. 9 of these articles assessed autonomic dysfunction using functional variables and 7 assessed autonomic dysfunction using physiological variables. Some studies included both functional and physiological variables. Of the nine studies linking autonomic dysfunction to functional variables, nine included heart rate variability (HRV), three included baroreflex sensitivity (BRS), and two included blood pressure variability (BPV). A total of 2714 adult patients were studied. Although the nature of association between autonomic dysfunction and outcome is unclear, the objective quantification of autonomic dysfunction seems to be associated with global patient outcome and other neurophysiological measures. Further studies are needed to validate its use and explore the underlying molecular mechanisms of the described associations.

Background Research efforts have been focused on limiting secondary injury after traumatic spinal cord injury by performing spinal decompression and early optimization of spinal cord perfusion. The Winnipeg Intraspinal Pressure Monitoring Study (WISP) was designed to validate the technique of intraspinal pressure monitoring at the site of injury using a fiberoptic pressure monitor placed at the site of injury. Objectives To describe the design of the WISP study. Study design Descriptive. Methods We explain the current limitations in the available scientific literature around the topic of blood pressure management for acute traumatic spinal cord injury and rational for the WISP study. Then, we describe the design of WISP including the patient selection criteria, study interventions, follow up schedules and outcome measurements. A multitude of future research avenues are also discussed. Results The WISP study is a single center pilot study designed to validate the technique of intraspinal pressure monitoring following acute traumatic spinal cord injury. The study involves the measurement of intraspinal pressure from within the subarachnoid space at the site of injury to derive a number of physiological parameters including spinal cord perfusion pressure, spinal cord blood volume, measures of spinal cord compliance and vascular reactivity indices. Twenty eligible patients will be recruited and followed for a period of 12 months with visits scheduled for the first 5 days and 1, 3, 6, and 12 months following surgical intervention. Conclusions The WISP study will provide the first attempt in North America at validation of intraspinal pressure monitoring with a fiberoptic pressure monitor at the site of injury. Successful validation will lead to future studies to define optimal spinal cord perfusion pressure, relationships of neural injury biomarkers and outcomes as well as epigenetic studies. Trial registration This study has been registered at clinicaltrials.gov (registration# NCT04550117).

Background A previous retrospective single-centre study suggested that the percentage of time spent with cerebral perfusion pressure (CPP) below the individual lower limit of reactivity (LLR) is associated with mortality in traumatic brain injury (TBI) patients. We aim to validate this in a large multicentre cohort. Methods Recordings from 171 TBI patients from the high-resolution cohort of the CENTER-TBI study were processed with ICM+ software. We derived LLR as a time trend of CPP at a level for which the pressure reactivity index (PRx) indicates impaired cerebrovascular reactivity with low CPP. The relationship with mortality was assessed with Mann-U test (first 7-day period), Kruskal–Wallis (daily analysis for 7 days), univariate and multivariate logistic regression models. AUCs (CI 95%) were calculated and compared using DeLong’s test. Results Average LLR over the first 7 days was above 60 mmHg in 48% of patients. %time with CPP < LLR could predict mortality (AUC 0.73, p  =  < 0.001). This association becomes significant starting from the third day post injury. The relationship was maintained when correcting for IMPACT covariates or for high ICP. Conclusions Using a multicentre cohort, we confirmed that CPP below LLR was associated with mortality during the first seven days post injury.

To describe the design of the WISP study. Descriptive. We explain the current limitations in the available scientific literature around the topic of blood pressure management for acute traumatic spinal cord injury and rational for the WISP study. Then, we describe the design of WISP including the patient selection criteria, study interventions, follow up schedules and outcome measurements. A multitude of future research avenues are also discussed. The WISP study is a single center pilot study designed to validate the technique of intraspinal pressure monitoring following acute traumatic spinal cord injury. The study involves the measurement of intraspinal pressure from within the subarachnoid space at the site of injury to derive a number of physiological parameters including spinal cord perfusion pressure, spinal cord blood volume, measures of spinal cord compliance and vascular reactivity indices. Twenty eligible patients will be recruited and followed for a period of 12 months with visits scheduled for the first 5 days and 1, 3, 6, and 12 months following surgical intervention. The WISP study will provide the first attempt in North America at validation of intraspinal pressure monitoring with a fiberoptic pressure monitor at the site of injury. Successful validation will lead to future studies to define optimal spinal cord perfusion pressure, relationships of neural injury biomarkers and outcomes as well as epigenetic studies.

Individualized cerebral perfusion pressure (CPP) targets may be derived via assessing the minimum of the parabolic relationship between an index of cerebrovascular reactivity and CPP. This minimum is termed the optimal CPP (CPPopt), and literature suggests that the further away CPP is from CPPopt, the worse is clinical outcome in adult traumatic brain injury (TBI). Typically, CPPopt estimation is based on intracranial pressure (ICP)-derived cerebrovascular reactivity indices, given ICP is commonly measured and provides continuous long duration data streams. The goal of this study is to describe for the first time the application of robotic transcranial Doppler (TCD) and the feasibility of determining CPPopt based on TCD autoregulation indices.

Abstract BACKGROUND Intracranial pressure (ICP) is a clinically important variable after severe traumatic brain injury (TBI) and has been monitored, along with clinical outcome, for over 25 yr in Addenbrooke's hospital, Cambridge, United Kingdom. This time period has also seen changes in management strategies with the implementation of protocolled specialist neurocritical care, expansion of neuromonitoring techniques, and adjustments of clinical treatment targets. OBJECTIVE To describe the changes in intracranial monitoring variables over the past 25 yr. METHODS Data from 1146 TBI patients requiring ICP monitoring were analyzed. Monitored variables included ICP, cerebral perfusion pressure (CPP), and the cerebral pressure reactivity index (PRx). Data were stratified into 5-yr epochs spanning the 25 yr from 1992 to 2017. RESULTS CPP increased sharply with specialist neurocritical care management (P < 0.0001) (introduction of a specific TBI management algorithm) before stabilizing from 2000 onwards. ICP decreased significantly over the 25 yr of monitoring from an average of 19 to 12 mmHg (P < 0.0001) but PRx remained unchanged. The mean number of ICP plateau waves and the number of patients developing refractory intracranial hypertension both decreased significantly. Mortality did not significantly change in the cohort (22%). CONCLUSION We demonstrate the evolving trends in neurophysiological monitoring over the past 25 yr from a single, academic neurocritical care unit. ICP and CPP were responsive to the introduction of an ICP/CPP protocol while PRx has remained unchanged. Graphical Abstract Graphical Abstract

A scoping review of the literature was performed systematically on commonly described continuous autoregulation measurement techniques in adult traumatic brain injury (TBI) to provide an overview of methodology and comprehensive reference library of the available literature for each technique. Five separate small systematic reviews were conducted for each of the continuous techniques: pressure reactivity index (PRx), laser Doppler flowmetry (LDF), near infrared spectroscopy (NIRS) techniques, brain tissue oxygen tension (PbtO2), and thermal diffusion (TD) techniques. Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to December 2016), and reference lists of relevant articles were searched. A two-tier filter of references was conducted. The literature base identified from the individual searches was limited, except for PRx. The total number of articles using each of the five searched techniques for continuous autoregulation in adult TBI were: PRx (28), LDF (4), NIRS (9), PbtO2 (10), and TD (8). All continuous techniques described in adult TBI are based on moving correlation coefficients. The premise behind the calculation of these moving correlation coefficients focuses on the impact of slow fluctuations in either mean arterial pressure (MAP) or cerebral perfusion pressure (CPP) on some indirect measure of cerebral blood flow (CBF), such as: intracranial pressure (ICP), LDF, NIRS signals, PbtO2, or TD CBF. The thought is the correlation between a hemodynamic driving factor, such as MAP or CPP, and a surrogate for CBF or cerebral perfusion sheds insight on the state of cerebral autoregulation. Both PRx and NIRS indices were validated experimentally against the “gold standard” static autoregulatory curve (Lassen curve) at least around the lower threshold of autoregulation. The PRx has the largest literature base supporting the association with patient outcome. Various methods of continuous autoregulation assessment are described within the adult TBI literature. Many studies exist on these various indices, suggesting an association between their values and patient morbidity/death.

The aim of this work was to explore the relationship between intracranial pressure (ICP)-derived indices of cerebrovascular reactivity and the lower limit of autoregulation (LLA) during arterial hypotension. We retrospectively reviewed recorded physiological data from piglets that underwent controlled hypotension. Hypotension was induced by inflation of a balloon catheter in the inferior vena cava. ICP, cortical laser Doppler flowmetry (LDF), and arterial blood pressure (ABP) monitoring was conducted. ICP-derived indices were calculated: 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 cerebral perfusion pressure [CPP]). LLA was estimated by piece-wise linear regression of CPP versus LDF. We produced error bar plots for PRx, PAx, and RAC against 5-mm Hg bins of CPP, displaying the relationship with the LLA. We compared CPP values at clinically relevant thresholds of PRx, PAx, and RAC to CPP measured at the LLA. Receiver operating curve (ROC) analysis was performed for each index across the LLA using 5-mm Hg bins for CPP. Mean LLA was 36.2 ± 10.5 mm Hg. Error bar plots demonstrated that PRx, PAx, and RAC increased, with CPP decreasing below the LLA. CPP at clinically relevant thresholds for PRx, PAx, and RAC displayed weak associations with the LLA, indicating that thresholds defined in TBI may not apply to a model of arterial hypotension. ROC analysis indicated that PRx, PAx, and RAC predicted the LLA, with AUCs of: 0.806 (95% confidence interval [CI], 0.750–0.863; p < 0.0001), 0.726 (95% CI, 0.664–0.789; p < 0.0001), and 0.710 (95% CI, 0.646–0.775; p < 0.0001), respectively. Three ICP-derived continuous indices of cerebrovascular reactivity, PRx, PAx, and RAC, were validated against the LLA within this experimental model of arterial hypotension, with PRx being superior.

Abstract IntroductionMultimodality monitoring of patients with severe traumatic brain injury (TBI) is primarily performed in neuro-critical care units to prevent secondary harmful brain insults and facilitate patient recovery. Several metrics are commonly monitored using both invasive and non-invasive techniques. The latest Brain Trauma Foundation guidelines from 2016 provide recommendations and thresholds for some of these. Still, high-level evidence for several metrics and thresholds is lacking.MethodsRegarding invasive brain monitoring, intracranial pressure (ICP) forms the cornerstone, and pressures above 22 mmHg should be avoided. From ICP, cerebral perfusion pressure (CPP) (mean arterial pressure (MAP)–ICP) and pressure reactivity index (PRx) (a correlation between slow waves MAP and ICP as a surrogate for cerebrovascular reactivity) may be derived. In terms of regional monitoring, partial brain tissue oxygen pressure (PbtO2) is commonly used, and phase 3 studies are currently ongoing to determine its added effect to outcome together with ICP monitoring. Cerebral microdialysis (CMD) is another regional invasive modality to measure substances in the brain extracellular fluid. International consortiums have suggested thresholds and management strategies, in spite of lacking high-level evidence. Although invasive monitoring is generally safe, iatrogenic hemorrhages are reported in about 10% of cases, but these probably do not significantly affect long-term outcome. Non-invasive monitoring is relatively recent in the field of TBI care, and research is usually from single-center retrospective experiences. Near-infrared spectrometry (NIRS) measuring regional tissue saturation has been shown to be associated with outcome. Transcranial doppler (TCD) has several tentative utilities in TBI like measuring ICP and detecting vasospasm. Furthermore, serial sampling of biomarkers of brain injury in the blood can be used to detect secondary brain injury development.ConclusionsIn multimodal monitoring, the most important aspect is data interpretation, which requires knowledge of each metric’s strengths and limitations. Combinations of several modalities might make it possible to discern specific pathologic states suitable for treatment. However, the cost–benefit should be considered as the incremental benefit of adding several metrics has a low level of evidence, thus warranting additional research.