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.

Prospective Pilot Clinical Study of Noninvasive Cerebrovascular Autoregulation Monitoring in Open-Angle Glaucoma Patients and Healthy Subjects.

PURPOSE: To analyze the cerebrovascular autoregulation (CA) dynamics in patients with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) as well as healthy subjects using noninvasive ultrasound technologies for the first time. METHODS: The CA status of 10 patients with NTG, 8 patients with HTG, and 10 healthy subjects was assessed, using an innovative noninvasive ultrasonic technique, based on intracranial blood volume slow-wave measurements. Identified in each participant were intraocular pressure, ocular perfusion pressure, and CA-related parameter volumetric reactivity index (VRx), as well as the duration and doses of the longest cerebral autoregulation impairment (LCAI). In addition, we calculated the associations of these parameters with patients' diagnoses. RESULTS: The VRx value, the LCAI dose, and duration in healthy subjects were significantly lower than in patients with NTG (P < 0.05). However, no significant differences were noted in these parameters between healthy subjects and HTG and between NTG and HTG groups. CONCLUSIONS: NTG is associated with the disturbed cerebral blood flow and could be diagnosed by performing noninvasive CA assessments. TRANSLATIONAL RELEVANCE: The VRx monitoring method can be applied to a wider range of patient groups, especially patients with normal-tension glaucoma.

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.

A comparative study of methods used to generate the arterial fiber structure in a clinically relevant numerical analysis.

The advanced constitutive material models of artery wall require the definition of the mean collagen fiber directions in the material configuration. There are several proposed methods; however, it is unclear how much does the fiber structures obtained by these methods differ one from the other and how much this difference may affect the results of the structural analysis of a clinically relevant scenario. Therefore, in this paper, we address this issue by presenting the results of the comparative study of our developed and currently state-of-the-art fiber definition methods. In addition, we present the verification of our developed numerical model that incorporates the extended Holzapfel-Gasser-Ogden (HGO) constitutive material model and the generalized prestressing algorithm (GPA). In the case of the patient-specific internal carotid artery (ICA), the percentage error of the mean fiber directions defined by different methods does not exceed 17.73% (at least 0.05%, at most 81.82%) and has negligible effect on the stress levels, as the percentage error of the mean circumferential Cauchy stress does not exceed 0.1%. Both fiber definition methods produce comparable fiber structure, but our proposed method has an advantage, as it does not depend on method and software used to model the arterial wall mechanics.

Cerebrovascular autoregulation impairments during cardiac surgery with cardiopulmonary bypass are related to postoperative cognitive deterioration: prospective observational study.

BACKGROUND: Postoperative cognitive dysfunction (POCD) occurs in approximately 33-83% of patients after cardiac surgery with cardiopulmonary bypass (CPB). Recent clinical data suggest that real-time, intraoperative monitoring of patient-specific cerebrovascular autoregulation (CA) may help to prevent POCD by detecting individual critical limits for mean arterial pressure (MAP) outside which CA is impaired. Objectives of the study were to detect the episodes of impaired CA during cardiac surgery with CPB, and to investigate the association between CA impairment and POCD. METHODS: The observational study of non-invasive ultrasonic volumetric CA monitoring included 59 patients undergoing elective coronary artery bypass graft surgery with CPB. All patients underwent series of neuropsychological tests the day before and ten days after the surgery in order to evaluate cognitive function. RESULTS: Twenty-two patients (37%) experienced POCD, 37 patients (63%) showed no cognitive deterioration. The duration of the single longest CA impairment event was found reliably associated with occurrence of POCD (P<0.05). The critical duration of the single longest CA impairment event was 5.03 minutes (odds ratio 14.5; CI 3.9-51.8) for studied population. CONCLUSIONS: Prospective clinical study showed that single longest CA impairment may result in post-operative deterioration of mental abilities. The duration of the single longest CA impairment event is the risk factor that is associated with POCD.

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.

Noninvasive monitoring of cerebrovascular autoregulation response to resistance exercises.

BACKGROUND AND OBJECTIVE. A novel noninvasive monitor is presented by demonstrating its capabilities to perform the real-time estimation of dynamics in cerebrovascular autoregulation in athletes during their training. The aim was to explore the characteristics of human cerebrovascular autoregulation by performing the monitoring of cerebrovascular autoregulation responses to resistance exercises in healthy volunteer athletes. MATERIAL AND METHODS. Cerebrovascular autoregulation status was monitored in 20 amateur and 20 elite male athletes (weightlifters and bodybuilders) in the supine position at rest during and after the resistance exercises by using a novel noninvasive monitor "Vittamed." Blood pressure and heart rate were also measured noninvasively. During the exercises, the athletes lifted 50 kg and 80% of 1RM (repetition maximum) weights in a dynamic and static manner in separate tests. RESULTS. The cerebrovascular autoregulation reactivity index showed a temporal improvement in the cerebrovascular autoregulation status for almost all sportsmen after the exercises. No disturbances of cerebrovascular autoregulation response occurred in the weightlifters and amateur athletes after the static and dynamic exercises. However, an unstable status of cerebrovascular autoregulation was observed for the elite bodybuilders during the interval of 400 to 600 s after the exercises. CONCLUSIONS. The data of this study demonstrated significant differences in cerebrovascular autoregulation response to the resistance exercises between the elite bodybuilders and other subjects (amateurs and weightlifters) - a temporarily unstable status of cerebrovascular autoregulation was observed in the group of elite bodybuilders. This study also demonstrated the applicability of the noninvasive device for exploring the physiology of cerebrovascular autoregulation mechanism in elite athletes and healthy volunteers.

Implementation of non-invasive brain physiological monitoring concepts.

The paper presents innovative methods and technology for non-invasive intracranial hemodynamics monitoring based on the measurement of brain parenchyma acoustic properties. The clinical investigation of new technology shows the similarity between the invasively recorded intracranial pressure (ICP) and non-invasively recorded intracranial blood volume (IBV) pulse waves, slow waves and slow trends under intensive care unit (ICU) conditions. Also, the applicability of the non-invasive IBV slow wave monitoring technique for cerebrovascular autoregulation non-invasive long-term monitoring is demonstrated by theoretical and experimental studies.

Investigation of intracranial media ultrasonic monitoring model.

The objectives are to investigate the peculiarities of the ultrasound pulse propagation through human extra/intracranial media by mathematical simulation and to confirm the simulation results experimentally by proving the suitability of the ultrasonic time-of-flight measurement method for human intracranial media (IM) physiological non-invasive monitoring. The mathematical model of ultrasound pulse propagation through the human extra/intracranial media is described. The simulation of various physiological phenomena were performed to determine the relationship between the characteristics of the transmitted ultrasound pulse through the human head and the acoustic properties of the IM. It is shown that non-invasive monitoring of the IM acoustic properties is possible by measuring the changes of the ultrasonic signal time-of-flight and the oscillation period. The influence made by variations in acoustic parameters of the external tissue/skull bones on the non-invasive measurement data is investigated and methods of compensation of that influence are presented. The models were applied for developing of a new non-invasive sonographic intracranial pressure (ICP) monitor (Vittamed). Comparative studies of this monitor with the invasive ICP monitor (Camino) have shown the possibility of achieving clinically acceptable accuracy of the long term non-invasive ICP monitoring of head injured patients in intensive care units.