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PurposeCPPopt denotes a Cerebral Perfusion Pressure (CPP) value at which the Pressure-Reactivity index, reflecting the global state of Cerebral Autoregulation, is best preserved. CPPopt has been investigated as a potential dynamically individualised CPP target in traumatic brain injury patients admitted in intensive care unit. The prospective bedside use of the concept requires ensured safety and reliability of the CPP recommended targets based on the automatically-generated CPPopt. We aimed to: Increase stability and reliability of the CPPopt automated algorithm by fine-tuning; perform outcome validation of the adjusted algorithm in a multi-centre TBI cohort.MethodsICM + software was used to derive CPPopt and fine-tune the algorithm. Parameters for improvement of the algorithm were selected based on qualitative and quantitative assessment of stability and reliability metrics. Patients enrolled in the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution cohort were included for retrospective validation. Yield and stability of the new algorithm were compared to the previous algorithm using Mann-U test. Area under the curves for mortality prediction at 6 months were compared with the DeLong Test.ResultsCPPopt showed higher stability (p < 0.0001), but lower yield compared to the previous algorithm [80.5% (70-87.5) vs 85% (75.7-91.2), p < 0.001]. Deviation of CPPopt could predict mortality with an AUC of [AUC = 0.69 (95% CI 0.59-0.78), p < 0.001] and was comparable with the previous algorithm.ConclusionThe CPPopt calculation algorithm was fine-tuned and adapted for prospective use with acceptable lower yield, improved stability and maintained prognostic power.

Funder: Stockholms Läns Landsting; doi: http://dx.doi.org/10.13039/501100004348, Funder: Familjen Erling-Perssons Stiftelse; doi: http://dx.doi.org/10.13039/100007436, Funder: Strategic Research Area Neuroscience, Funder: Karolinska Institute, INTRODUCTION: Multimodality 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. METHODS: Regarding 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. CONCLUSIONS: In 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.

Background Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty. Aim To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities. Methods A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants. Results Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence. Conclusion The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.

Impaired cerebrovascular reactivity in adult moderate and severe traumatic brain injury (TBI) is known to be associated with worse global outcome at 6-12 months. As technology has improved over the past decades, monitoring of cerebrovascular reactivity has shifted from intermittent measures, to experimentally validated continuously updating indices at the bedside. Such advances have led to the exploration of individualised physiologic targets in adult TBI management, such as optimal cerebral perfusion pressure (CPP) values, or CPP limits in which vascular reactivity is relatively intact. These targets have been shown to have a stronger association with outcome compared with existing consensus-based guideline thresholds in severe TBI care. This has sparked ongoing prospective trials of such personalised medicine approaches in adult TBI. In this narrative review paper, we focus on the concept of cerebral autoregulation, proposed mechanisms of control and methods of continuous monitoring used in TBI. We highlight multimodal cranial monitoring approaches for continuous cerebrovascular reactivity assessment, physiologic and neuroimaging correlates, and associations with outcome. Finally, we explore the recent 'state-of-the-art' advances in personalised physiologic targets based on continuous cerebrovascular reactivity monitoring, their benefits, and implications for future avenues of research in TBI.

Summary Impaired cerebrovascular reactivity in adult moderate and severe traumatic brain injury (TBI) is known to be associated with worse global outcome at 6–12 months. As technology has improved over the past decades, monitoring of cerebrovascular reactivity has shifted from intermittent measures, to experimentally validated continuously updating indices at the bedside. Such advances have led to the exploration of individualised physiologic targets in adult TBI management, such as optimal cerebral perfusion pressure (CPP) values, or CPP limits in which vascular reactivity is relatively intact. These targets have been shown to have a stronger association with outcome compared with existing consensus-based guideline thresholds in severe TBI care. This has sparked ongoing prospective trials of such personalised medicine approaches in adult TBI. In this narrative review paper, we focus on the concept of cerebral autoregulation, proposed mechanisms of control and methods of continuous monitoring used in TBI. We highlight multimodal cranial monitoring approaches for continuous cerebrovascular reactivity assessment, physiologic and neuroimaging correlates, and associations with outcome. Finally, we explore the recent ‘state-of-the-art' advances in personalised physiologic targets based on continuous cerebrovascular reactivity monitoring, their benefits, and implications for future avenues of research in TBI.

Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, and poses a substantial public health burden. TBI is increasingly documented not only as an acute condition but also as a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration. The first Lancet Neurology Commission on TBI, published in 2017, called for a concerted effort to tackle the global health problem posed by TBI. Since then, funding agencies have supported research both in high-income countries (HICs) and in low-income and middle-income countries (LMICs). In November 2020, the World Health Assembly, the decision-making body of WHO, passed resolution WHA73.10 for global actions on epilepsy and other neurological disorders, and WHO launched the Decade for Action on Road Safety plan in 2021. New knowledge has been generated by large observational studies, including those conducted under the umbrella of the International Traumatic Brain Injury Research (InTBIR) initiative, established as a collaboration of funding agencies in 2011. InTBIR has also provided a huge stimulus to collaborative research in TBI and has facilitated participation of global partners. The return on investment has been high, but many needs of patients with TBI remain unaddressed. This update to the 2017 Commission presents advances and discusses persisting and new challenges in prevention, clinical care, and research.

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.

Background Continuous monitoring of cerebral autoregulation is considered clinically useful due to its ability to warn against brain ischemic insults, which may translate to a relationship with adverse outcome. It is typically performed using the pressure reactivity index (PRx) based on mean arterial pressure and intracranial pressure. A new ORx index based on brain tissue oxygenation and cerebral perfusion pressure (CPP) has been proposed that similarly allows for evaluation of cerebrovascular reactivity. Conflicting results exist concerning its clinical utility.Methods Retrospective analysis was performed in 85 patients with traumatic brain injury (TBI). ORx was calculated using three time windows of 5, 20, and 60 min. Correlation coefficients and individual "optimal CPP'' (CPPopt) were calculated using both PRx and ORx, and relation to patient outcome investigated.Results Correlation coefficients for all comparisons between PRx and ORx indicated poor association between these indices (range from -0.04 to 0.07). PRx was significantly lower in patients with good outcome (p = 0.01), while none of the ORx indices proved to be significantly different in the two outcome groups. Higher mortality related to average CPP Conclusion In the TBI setting, ORx does not appear to correlate with vascular pressure reactivity as assessed with PRx. Its potential use for individualizing CPP thresholds remains unclear.

Objective: Acute intracranial hypertension is an important risk factor of secondary brain damage after traumatic brain injury. Hypertensive episodes are often diagnosed reactively, leading to late detection and lost time for intervention planning. A pro-active approach that predicts critical events several hours ahead of time could assist in directing attention to patients at risk. Approach: We developed a prediction framework that forecasts onsets of acute intracranial hypertension in the next 8 hours. It jointly uses cerebral auto-regulation indices, spectral energies and morphological pulse metrics to describe the neurological state of the patient. One-minute base windows were compressed by computing signal metrics, and then stored in a multi-scale history, from which physiological features were derived. Main results: Our model predicted events up to 8 hours in advance with alarm recall rates of 90% at a precision of 30.3% in the MIMIC-III waveform database, improving upon two baselines from the literature. We found that features derived from high-frequency waveforms substantially improved the prediction performance over simple statistical summaries of low-frequency time series, and each of the three feature classes contributed to the performance gain. The inclusion of long-term history up to 8 hours was especially important. Significance: Our results highlight the importance of information contained in high-frequency waveforms in the neurological intensive care unit. They could motivate future studies on pre-hypertensive patterns and the design of new alarm algorithms for critical events in the injured brain., 11 pages, 5 figures

Acta neurochirurgica 161(9), 1955-1964 (2019). doi:10.1007/s00701-019-03980-8, Published by Springer, Wien [u.a.]

Acta neurochirurgica 161(6), 1217-1227 (2019). doi:10.1007/s00701-019-03844-1 special issue: "Brain trauma", Published by Springer, Wien [u.a.]

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.

Introduction Multimodality monitoring is regularly employed in adult traumatic brain injury (TBI) patients where it provides physiologic and therapeutic insight into this heterogeneous condition. Pediatric studies are less frequent. Methods An analysis of data collected prospectively from 12 pediatric TBI patients admitted to Addenbrooke's Hospital, Pediatric Intensive Care Unit (PICU) between August 2012 and December 2014 was performed. Patients' intracranial pressure (ICP), mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) were monitored continuously using brain monitoring software ICM+(R)) Pressure reactivity index (PRx) and 'Optimal CPP' (CPPopt) were calculated. Patient outcome was dichotomized into survivors and non-survivors. Results At 6 months 8/12 (66%) of the cohort survived the TBI. The median (+/- IQR) ICP was significantly lower in survivors 13.1 +/- 3.2 mm Hg compared to non-survivors 21.6 +/- 42.9 mm Hg (p = 0.003). The median time spent with ICP over 20 mm Hg was lower in survivors (9.7+ 9.8% vs 60.5 + 67.4% in non-survivors; p = 0.003). Although there was no evidence that CPP was different between survival groups, the time spent with a CPP close (within 10 mm Hg) to the optimal CPP was significantly longer in survivors (90.7 +/- 12.6%) compared with non-survivors (70.6 +/- 21.8%; p = 0.02). PRx provided significant outcome separation with median PRx in survivors being 0.02 +/- 0.19 compared to 0.39 +/- 0.62 in non-survivors (p = 0.02). Conclusion Our observations provide evidence that multi-modality monitoring may be useful in pediatric TBI with ICP, deviation of CPP from CPPopt, and PRx correlating with patient outcome.

Introduction Multimodality monitoring is regularly employed in adult traumatic brain injury (TBI) patients where it provides physiologic and therapeutic insight into this heterogeneous condition. Pediatric studies are less frequent. Methods An analysis of data collected prospectively from 12 pediatric TBI patients admitted to Addenbrooke's Hospital, Pediatric Intensive Care Unit (PICU) between August 2012 and December 2014 was performed. Patients' intracranial pressure (ICP), mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) were monitored continuously using brain monitoring software ICM+(R)) Pressure reactivity index (PRx) and 'Optimal CPP' (CPPopt) were calculated. Patient outcome was dichotomized into survivors and non-survivors. Results At 6 months 8/12 (66%) of the cohort survived the TBI. The median (+/- IQR) ICP was significantly lower in survivors 13.1 +/- 3.2 mm Hg compared to non-survivors 21.6 +/- 42.9 mm Hg (p = 0.003). The median time spent with ICP over 20 mm Hg was lower in survivors (9.7+ 9.8% vs 60.5 + 67.4% in non-survivors; p = 0.003). Although there was no evidence that CPP was different between survival groups, the time spent with a CPP close (within 10 mm Hg) to the optimal CPP was significantly longer in survivors (90.7 +/- 12.6%) compared with non-survivors (70.6 +/- 21.8%; p = 0.02). PRx provided significant outcome separation with median PRx in survivors being 0.02 +/- 0.19 compared to 0.39 +/- 0.62 in non-survivors (p = 0.02). Conclusion Our observations provide evidence that multi-modality monitoring may be useful in pediatric TBI with ICP, deviation of CPP from CPPopt, and PRx correlating with patient outcome.

One of the predictive factors of outcome in traumatic brain injury is high intracranial pressure (ICP). Recently, the time course of ICP has been described but few data are available on the relation of these ICP profiles and outcome. The aim of this study is to investigate the relation of the time course of ICP with CT-findings and outcome.Retrospective analysis of prospectively collected data of 246 patients with traumatic brain injury admitted to the neurosurgical intensive care unit.Early rise in ICP (within the first 2 days) was present in 32%, an intermediate rise (between days 3 and 5) in 34% and a late rise (after day 5) in 34% of patients. Half of the patients with a normal opening pressure (76%) developed intermediate or late ICP rise profiles. More mass lesions and sub/epidural hematomas were present in the late rise group. Patients with a late ICP rise required significant more intensive treatment (65% vs. 37 and 33%) when compared to the early and intermediate rise groups. In multiple regression analysis both ICP profiles and extracranial hematomas were related to outcome. With late ICP rise more unfavorable outcome (46 vs. 17%, P During ICP monitoring different ICP profiles are present over time. These profiles are related to CT-characteristics and outcome. The importance of early and late monitoring of ICP is underlined.

Secondary insults occuring after injury have been prospectively assessed in seven head-injured patients who required intrahospital transfer to a computerized tomography unit for re-evaluation of their brain injury. During transportation the intracranial pressure, blood pressure. and arterial blood gases were monitored. A significant increase in intracranial pressure was observed during transport (p < 0.01). The conclusion is that patients should be ventilated and have appropriate sedation and analgesia. This could provide some protection against secondary insults.