Cerebrospinal fluid volume as an early radiological factor for clinical course prediction after aneurysmal subarachnoid hemorrhage. A pilot study.

BACKGROUND: The pathological mechanisms following aneurysmal subarachnoid hemorrhage (SAH) are poorly understood. Limited clinical evidence exists on the association between cerebrospinal fluid (CSF) volume and the risk of delayed cerebral ischemia (DCI) or cerebral vasospasm (CV). In this study, we raised the hypothesis that the amount of CSF or its ratio to hemorrhage blood volume, as determined from non-contrast Computed Tomography (NCCT) images taken on admission, could be a significant predictor for CV and DCI. METHODS: The pilot study included a retrospective analysis of NCCT scans of 49 SAH patients taken shortly after an aneurysm rupture (33 males, 16 females, mean age 56.4 ± 15 years). The SynthStrip and Slicer3D software tools were used to extract radiological factors - CSF, brain, and hemorrhage volumes from the NCCT images. The "pure" CSF volume (VCSF) was estimated in the range of [-15, 15] Hounsfield units (HU). RESULTS: VCSF was negatively associated with the risk of CV occurrence (p = 0.0049) and DCI (p = 0.0069), but was not associated with patients' outcomes. The hemorrhage volume (VSAH) was positively associated with an unfavorable outcome (p = 0.0032) but was not associated with CV/DCI. The ratio VSAH/VCSF was positively associated with, both, DCI (p = 0.031) and unfavorable outcome (p = 0.002). The CSF volume normalized by the brain volume showed the highest characteristics for DCI prediction (AUC = 0.791, sensitivity = 0.80, specificity = 0.812) and CV prediction (AUC = 0.769, sensitivity = 0.812, specificity = 0.70). CONCLUSION: It was demonstrated that "pure" CSF volume retrieved from the initial NCCT images of SAH patients (including CV, Non-CV, DCI, Non-DCI groups) is a more significant predictor of DCI and CV compared to other routinely used radiological biomarkers. VCSF could be used to predict clinical course as well as to personalize the management of SAH patients. Larger multicenter clinical trials should be performed to test the added value of the proposed methodology.

Impaired cerebral autoregulation detected in early prevasospasm period is associated with unfavorable outcome after spontaneous subarachnoid hemorrhage: an observational prospective pilot study.

BACKGROUND: Subarachnoid hemorrhage (SAH) patients with cerebral autoregulation (CA) impairment at an early post-SAH period are at high risk of unfavorable outcomes due to delayed cerebral ischemia (DCI) or other complications. Limited evidence exists for an association between early-stage CA impairments and SAH patient outcomes. The objective of this prospective study was to explore associations between CA impairments detected in early post-SAH snapshot examinations and patient outcomes. METHODS: The pilot observational study included 29 SAH patients whose CA status was estimated 2-3 days after spontaneous aneurysm rupture and a control group of 15 healthy volunteers for comparison. Inflatable leg recovery boots (reboots.com, Germany) were used for the safe controlled generation of arterial blood pressure (ABP) changes necessary for reliable CA examination. At least 5 inflation‒deflation cycles of leg recovery boots with a 2-3 min period were used during examinations. CA status was assessed according to the delay time (∆TCBFV) measured between ABP(t) and cerebral blood flow velocity (CBFV(t)) signals during artificially induced ABP changes at boot deflation cycle. CBFV was measured in middle cerebral artery by using transcranial Doppler device. RESULTS: Statistically significant differences in ∆TCBFV were found between SAH patients with unfavorable outcomes (∆TCBFV = 1.37 ± 1.23 s) and those with favorable outcomes (∆TCBFV = 2.86 ± 0.99 s) (p < 0.001). Early assessment of baroreflex sensitivity (BRS) during the deflation cycle showed statistically significant differences between the DCI and non-DCI patient groups (p = 0.039). CONCLUSIONS: A relatively small delay of ∆TCBFV <1.6 s between CBFV(t) and ABP(t) waves could be an early warning sign associated with unfavorable outcomes in SAH patients. The BRS during boot deflation can be used as a biomarker for the prediction of DCI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06028906. Registered 31 August 2023 - Retrospectively registered, https://www. CLINICALTRIALS: gov/study/NCT06028906 .

Feasibility of the optimal cerebral perfusion pressure value identification without a delay that is too long.

Optimal cerebral perfusion pressure (CPPopt)-targeted treatment of traumatic brain injury (TBI) patients requires 2-8 h multi-modal monitoring data accumulation to identify CPPopt value for individual patient. Minimizing the time required for monitoring data accumulation is needed to improve the efficacy of CPPopt-targeted therapy. A retrospective analysis of multimodal physiological monitoring data from 87 severe TBI patients was performed by separately representing cerebrovascular autoregulation (CA) indices in relation to CPP, arterial blood pressure (ABP), and intracranial pressure (ICP) to improve the existing CPPopt identification algorithms. Machine learning (ML)-based algorithms were developed for automatic identification of informative data segments that were used for reliable CPPopt, ABPopt, ICPopt and the lower/upper limits of CA (LLCA/ULCA) identification. The reference datasets of the informative data segments and, artifact-distorted segments, and the datasets of different clinical situations were used for training the ML-based algorithms, allowing us to choose the appropriate individualized CPP-, ABP- or ICP-guided management for 79% of the full monitoring time for the studied population. The developed ML-based algorithms allow us to recognize informative physiological ABP/ICP variations within 24 min intervals with an accuracy up to 79% (compared to the initial accuracy of 74%) and use these segments for timely optimal value identification or CA limits determination in CPP, ABP or ICP data. Prospective clinical studies are needed to prove the efficiency of the developed algorithms.

The Different Temozolomide Effects on Tumorigenesis Mechanisms of Pediatric Glioblastoma PBT24 and SF8628 Cell Tumor in CAM Model and on Cells In Vitro.

It is necessary to elucidate the individual effects of temozolomide (TMZ) on carcinogenesis and tumor resistance to chemotherapy mechanisms. The study aimed to investigate the TMZ 50 and 100 µM dose effect difference between PBT24 and SF8628 cell line high-grade pediatric glioblastoma (phGBM) xenografts in a chicken chorioallantoic membrane (CAM) model, on PCNA and EZH2 immunohistochemical expression in the tumor and on the expression of NKCC1, KCC2, E- and N-cadherin genes in TMZ-treated and control cell groups in vitro. TMZ at a 100 µg dose reduced the incidence of PBT24 xenograft invasion into the CAM, CAM thickening and the number of blood vessels in the CAM (p < 0.05), but did not affect the SF8628 tumor in the CAM model. The TMZ impact on PBT24 and SF8628 tumor PCNA expression was similarly significantly effective but did not alter EZH2 expression in the studied tumors. The TMZ at 50 µM caused significantly increased RNA expression of the NKCC1 gene in both studied cell types compared with controls (p < 0.05). The expression of the KCC2 gene was increased in PBT24 TMZ-treated cells (p < 0.05), and no TMZ effect was found in SF8628-treated cells. The study supports the suggestion that individual sensitivity to TMZ should be assessed when starting treatment.

Association Between the Cerebral Autoregulation Index (Pressure Reactivity), Patient's Clinical Outcome, and Quality of ABP(t) and ICP(t) Signals for CA Monitoring.

Background and Objectives: The aim of this study was to explore the association between the cerebral autoregulation (CA) index, the pressure reactivity index (PRx), the patient's clinical outcome, and the quality of arterial blood pressure (ABP(t)) and intracranial blood pressure (ICP(t)) signals by comparing two filtering methods to derive the PRx. Materials and Methods: Data from 60 traumatic brain injury (TBI) patients were collected. Moving averaging and FIR (Finite Impulse Response) filtering were performed on the ABP(t) and ICP(t) signals, and the PRx was estimated from both filtered datasets. Sensitivity, specificity, and receiver-operating characteristic (ROC) curves with the area under the curves (AUCs) were determined using patient outcomes as a reference. The outcome chosen for comparison among the two filtering methods were mortality and survival. Results: The FIR filtering approach, compared with clinical outcome, had a sensitivity of 70%, a specificity of 81%, and a level of significance p = 0.001 with an area under the curve (AUC) of 0.78. The moving average filtering method compared with the clinical outcome had a sensitivity of 58%, a specificity of 72%, and a level of significance p = 0.054, with an area under the curve (AUC) of 0.66. Conclusions: The FIR (optimal) filtering approach was found to be more sensitive for discriminating between two clinical outcomes, namely intact (survival) and impaired (death) cerebral autoregulation for TBI treatment decision making.

Optimal Cerebral Perfusion Pressure: Targeted Treatment for Severe Traumatic Brain Injury.

Identification of individual therapy targets is critical for traumatic brain injury (TBI) patients. Clinical outcomes depend on cerebrovascular autoregulation (CA) impairment. Here, we compare the effectiveness of optimal cerebral perfusion pressure (CPPopt)-targeted therapy in younger (<45 years of age) and elderly (≥45 years of age) TBI patients. Single-center multi-modal invasive arterial blood pressure(t), intracranial pressure (ICP)(t), cerebral perfusion pressure CPP(t), and CPPopt(t) monitoring (n = 81) was performed. ICM+ software was used for continuous CPPopt(t) status assessment by identification of pressure reactivity index (PRx). The most significant prognostic factors were age, Glasgow Coma Scale, serum glucose, and duration of longest CA ompairment event (LCAI) when PRx(t) >0.5 within 24 h after admission. The modeled accuracies for favorable and unfavorable outcome prediction were 86.5% and 90.9%, respectively. Age above 45 years and averaged ICP during all monitoring time above 21.3 mm Hg was associated with unfavorable outcome of an individual patient. Averaged CPP values close to CPPopt were associated with a better outcome in younger patients. Averaged ΔCPPopt <-5.0 mm Hg, averaged PRx >0.36, and LCAI >100 min were significantly associated with mortality for the younger patients. The critical values of averaged PRx >0.26 and LCAI >61 min were significantly associated with mortality for the elderly group. Autoregulation-guided treatment was important for individual TBI management, especially in younger patients. Further randomized multi-center studies are needed to prove final benefit.

Non-invasive Cerebrovascular Autoregulation Assessment Using the Volumetric Reactivity Index: Prospective Study.

BACKGROUND: This prospective study of an innovative non-invasive ultrasonic cerebrovascular autoregulation (CA) monitoring method is based on real-time measurements of intracranial blood volume (IBV) reactions following changes in arterial blood pressure. In this study, we aimed to determine the clinical applicability of a non-invasive CA monitoring method by performing a prospective comparative clinical study of simultaneous invasive and non-invasive CA monitoring on intensive care patients. METHODS: CA was monitored in 61 patients with severe traumatic brain injuries invasively by calculating the pressure reactivity index (PRx) and non-invasively by calculating the volumetric reactivity index (VRx) simultaneously. The PRx was calculated as a moving correlation coefficient between intracranial pressure and arterial blood pressure slow waves. The VRx was calculated as a moving correlation coefficient between arterial blood pressure and non-invasively-measured IBV slow waves. RESULTS: A linear regression between VRx and PRx averaged per patients' monitoring session showed a significant correlation (r = 0.843, p < 0.001; 95% confidence interval 0.751 - 0.903). The standard deviation of the difference between VRx and PRx was 0.192; bias was - 0.065. CONCLUSIONS: This prospective clinical study of the non-invasive ultrasonic volumetric reactivity index VRx monitoring, based on ultrasonic time-of-flight measurements of IBV dynamics, showed significant coincidence of non-invasive VRx index with invasive PRx index. The ultrasonic time-of-flight method reflects blood volume changes inside the acoustic path, which crosses both hemispheres of the brain. This method does not reflect locally and invasively-recorded intracranial pressure slow waves, but the autoregulatory reactions of both hemispheres of the brain. Therefore, VRx can be used as a non-invasive cerebrovascular autoregulation index in the same way as PRx and can also provide information about the CA status encompassing all intracranial hemodynamics.

Benefit on optimal cerebral perfusion pressure targeted treatment for traumatic brain injury patients.

PURPOSE: The maintenance of patient-specific optimal cerebral perfusion pressure (CPPopt) is crucial for patients with traumatic brain injury (TBI). The goal of the study was to explore the influence of CPP declination from CPPopt value on the TBI patients' outcome. METHODS: The CPP and cerebrovascular autoregulation (CA) monitoring of 52 TBI patients was performed. Patient-specific CPPopt has been identified and the associations between the patients' outcome and complex influence of time of CPP declination from CPPopt value, age, and the duration of CA impairment episodes has been analyzed. RESULTS: The multiple correlation coefficient between the Glasgow outcome scale (GOS), duration of CA impairment events and percentage time, when 0<ΔCPPopt<10mmHg was r=-0.643 (P<0.001). The multiple correlation coefficients between GOS, age, and percentage time of ΔCPPopt when 0<ΔCPPopt<10mmHg was r=-0.587 (P<0.001). CONCLUSION: The CPPopt-targeted patient-specific management might be useful for stabilizing CA in TBI patients as well as for improving their outcome. Better outcomes were obtained by maintaining CPP in light hyperperfusion condition (up to 10mmHg above CPPopt) when CPPopt is in the range of 60-80mmHg, and keeping CPP within the range of CPPopt +/-5mmHg when CPPopt is above 80mmHg.

Accuracy, Precision, Sensitivity, and Specificity of Noninvasive ICP Absolute Value Measurements.

An innovative absolute intracranial pressure (ICP) value measurement method has been validated by multicenter comparative clinical studies. The method is based on two-depth transcranial Doppler (TCD) technology and uses intracranial and extracranial segments of the ophthalmic artery as pressure sensors. The ophthalmic artery is used as a natural pair of "scales" that compares ICP with controlled pressure Pe, which is externally applied to the orbit. To balance the scales, ICP = Pe a special two-depth TCD device was used as a pressure balance indicator. The proposed method is the only noninvasive ICP measurement method that does not need patient-specific calibration.

Association between the outcome of traumatic brain injury patients and cerebrovascular autoregulation, cerebral perfusion pressure, age, and injury grades.

BACKGROUND AND OBJECTIVE: The aim of this study was to explore the association of cerebrovascular autoregulation (CA) and optimal cerebral perfusion pressure (CPP) managing conditions with the outcome of traumatic brain injury (TBI) patients including additional information about the patients' age and grade of diffuse axonal injury (DAI). MATERIALS AND METHODS: The CA monitoring of 28 TBI patients was performed by using ICM+ software (Cambridge, UK). The CA status estimating pressure reactivity indexes (PRx) and CPP data were processed in order to obtain information on the patient-specific treatment conditions by calculating the optimal CPP. RESULTS: There was a negative correlation between the Glasgow outcome scale (GOS) score and PRx (r=-0.448 at hospital discharge and r=-0.402 after 6 months). The estimated threshold value PRx of >0.24 was associated with mortality. The correlation coefficients between the GOS score and the difference CPP-optimal CPP were 0.549 at hospital discharge and 0.484 after 6 months. The threshold value of CPP declination from ΔCPPopt per -6mmHg was associated with mortality. Poorer outcome was predicted for elderly TBI patients (aged >47 years) and patients having a DAI grade of 3. CONCLUSIONS: The association of the GOS score with CPP, CA impairment conditions, age and diffuse axonal injury (DAI) grade showed that the outcomes of TBI patients were associated with patient-specific CPP management and better outcomes were obtained for younger patients, for patients having lower DAI grade and for patients whose CPP was kept within the range from the optimal CPP to the optimal CPP+10mmHg.

Association of Severe Traumatic Brain Injury Patient Outcomes With Duration of Cerebrovascular Autoregulation Impairment Events.

BACKGROUND: Cerebrovascular autoregulation (CA) is an important hemodynamic mechanism that protects the brain against inappropriate fluctuations in cerebral blood flow in the face of changing cerebral perfusion pressure. Temporal CA failure is associated with worse outcomes in various acute neurological diseases. An integrative approach is presently used according to the existing paradigm for the association of series of temporal CA impairments with the outcomes of patients with traumatic brain injury (TBI). OBJECTIVE: To explore the influence of the duration of CA impairment events on severe TBI patient outcomes. Patient age was also included in the analysis of the prospectively collected clinical data. METHODS: CA monitoring included 33 prospective severe TBI patients. The pressure reactivity index [PRx(t)] was continuously monitored to collect information on the dynamics of CA status and to analyze associations between the duration of the longest CA impairment event and patient outcomes. RESULTS: The Glasgow outcome scale and the duration of the longest CA impairment were negatively correlated. The duration of autoregulation impairment significantly correlated with worse outcomes. Multidimensional representation of Glasgow outcome scale plots showed that better outcomes were obtained for younger patients (age < 47 years) and those whose longest CA impairment event was shorter than 40 minutes if PRx(t) was above 0.7 in the CA impairment event. CONCLUSION: Unfavorable outcomes for TBI patients are more significantly associated with the duration of the single longest CA impairment episode at a high PRx(t) value, rather than with averaged PRx(t) values or the average time of all CA impairment episodes. ABBREVIATIONS: ABP, arterial blood pressureABP(t), continuous reference arterial blood pressureCA, cerebrovascular autoregulationCBF, cerebral blood flowCPP, cerebral perfusion pressureGOS, Glasgow outcome scaleGOSHD, Glasgow outcome scale after hospital dischargeGOS6M, Glasgow outcome scale at 6 months after dischargeICP, intracranial pressureICP(t), continuously monitored intracranial pressureLCAI, longest CA impairmentoptCPP, optimal cerebral perfusion pressurePRx(t), pressure reactivity indexTBI, traumatic brain injury.