Pulse Amplitude Index Research Articles

Time spent above optimal cerebral perfusion pressure is not associated with failure to improve in outcome in traumatic brain injury

BackgroundOptimal cerebral perfusion pressure (CPPopt) has emerged as a promising personalized medicine approach to the management of moderate-to-severe traumatic brain injury (TBI). Though literature demonstrating its association with poor outcomes exists, there is yet to be work done on its association with outcome transition due to a lack of serial outcome data analysis. In this study we investigate the association between various metrics of CPPopt and failure to improve in outcome over time.MethodsCPPopt was derived using three different cerebrovascular reactivity indices; the pressure reactivity index (PRx), the pulse amplitude index (PAx), and the RAC index. For each index, % times spent with cerebral perfusion pressure (CPP) above and below its CPPopt and upper and lower limits of reactivity were calculated. Patients were dichotomized based on improvement in Glasgow Outcome Scale-Extended (GOSE) scores into Improved vs. Not Improved between 1 and 3 months, 3 and 6 months, and 1- and 6-month post-TBI. Logistic regression analyses were then conducted, adjusting for the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) variables.ResultsThis study included a total of 103 patients from the Winnipeg Acute TBI Database. Through Mann–Whitney U testing and logistic regression analysis, it was found that % time spent with CPP below CPPopt was associated with failure to improve in outcome, while % time spent with CPP above CPPopt was generally associated with improvement in outcome.ConclusionsOur study supports the existing narrative that time spent with CPP below CPPopt results in poorer outcomes. However, it also suggests that time spent above CPPopt may not be associated with worse outcomes and is possibly even associated with improvement in outcome.

Intracranial Pressure-Derived Cerebrovascular Reactivity Indices and Their Critical Thresholds: A Canadian High Resolution-Traumatic Brain Injury Validation Study.

Current neurointensive care guidelines recommend intracranial pressure (ICP) and cerebral perfusion pressure (CPP) centered management for moderate-severe traumatic brain injury (TBI) because of their demonstrated associations with patient outcome. Cerebrovascular reactivity metrics, such as the pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC index, have also demonstrated significant prognostic capabilities with regard to outcome. However, critical thresholds for cerebrovascular reactivity indices have only been identified in two studies conducted at the same center. In this study, we aim to determine the critical thresholds of these metrics by leveraging a unique multi-center database. The study included a total of 354 patients from the CAnadian High-Resolution TBI (CAHR-TBI) Research Collaborative. Based on 6-month Glasgow Outcome Scores, patients were dichotomized into alive versus dead and favorable versus unfavorable. Chi-square values were then computed for incrementally increasing values of each physiological parameter of interest against outcome. The values that generated the greatest chi-squares for each parameter were considered to be the thresholds with the greatest outcome discriminatory capacity. To confirm that the identified thresholds provide prognostic utility, univariate and multivariable logistical regression analyses were performed adjusting for the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) variables. Through the chi-square analysis, a lower limit CPP threshold of 60 mm Hg and ICP thresholds of 18 mm Hg and 22 mm Hg were identified for both survival and favorable outcome predictions. For the cerebrovascular reactivity metrics, different thresholds were identified for the two outcome dichotomizations. For survival prediction, thresholds of 0.35, 0.25, and 0 were identified for PRx, PAx, and RAC, respectively. For favorable outcome prediction, thresholds of 0.325, 0.20, and 0.05 were found. Univariate logistical regression analysis demonstrated that the time spent above/below thresholds were associated with outcome. Further, multivariable logistical regression analysis found that percent time above/below the identified thresholds added additional variance to the IMPACT core model for predicting both survival and favorable outcome. In this study, we were able to validate the results of the previous two works as well as to reaffirm the ICP and CPP guidelines from the Brain Trauma Foundation (BTF) and the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC).

Modifications of peripheral perfusion in patients with vasopressor-dependent septic shock treated with polymyxin B-direct hemoperfusion

Abnormal peripheral perfusion (PP) worsens the prognosis of patients with septic shock. Polymyxin B-direct hemoperfusion (PMX-DHP) increases blood pressure and reduces vasopressor doses. However, the modification of PP following administration of PMX-DHP in patients with vasopressor-dependent septic shock have not yet been elucidated. A retrospective exploratory observational study was conducted in patients with septic shock treated with PMX-DHP. Pulse-amplitude index (PAI), vasoactive inotropic score (VIS), and cumulative fluid balance data were extracted at PMX-DHP initiation (T0) and after 24 (T24) and 48 (T48) h. Changes in these data were analyzed in all patients and two subgroups (abnormal PP [PAI < 1] and normal PP [PAI ≥ 1]) based on the PAI at PMX-DHP initiation. Overall, 122 patients (abnormal PP group, n = 67; normal PP group, n = 55) were evaluated. Overall and in the abnormal PP group, PAI increased significantly at T24 and T48 compared with that at T0, with a significant decrease in VIS. Cumulative 24-h fluid balance after PMX-DHP initiation was significantly higher in the abnormal PP group. PMX-DHP may be an effective intervention to improve PP in patients with abnormal PP; however, caution should be exercised as fluid requirements may differ from that of patients with normal PP.

Cerebrovascular Reactivity Is Not Associated With Therapeutic Intensity in Adult Traumatic Brain Injury: A Validation Study.

Within traumatic brain injury (TBI) care, there is growing interest in pathophysiological markers as surrogates of disease severity, which may be used to improve and individualize care. Of these, assessment of cerebrovascular reactivity (CVR) has been extensively studied given that it is a consistent, independent factor associated with mortality and functional outcome. However, to date, the literature supports little-to-no impact of current guideline-supported therapeutic interventions on continuously measured CVR. Previous work in this area has suffered from a lack of validation studies, given the rarity of time-matched high-frequency cerebral physiology with serially recorded therapeutic interventions; thus, we undertook a validation study. Utilizing the Winnipeg Acute TBI database, we evaluated the association between daily treatment intensity levels, as measured through the therapeutic intensity level (TIL) scoring system, and continuous multi-modal-derived CVR measures. CVR measures included the intracranial pressure (ICP)-derived pressure reactivity index, pulse amplitude index, and RAC index (a correlation between the pulse amplitude of ICP and cerebral perfusion pressure), as well as the cerebral autoregulation measure of near-infrared spectroscopy-based cerebral oximetry index. These measures were also derived over a key threshold for each day and were compared to the daily total TIL measure. In summary, we could not observe any overall relationship between TIL and these CVR measures. This validates previous findings and represents only the second such analysis to date. This helps to confirm that CVR appears to remain independent of current therapeutic interventions and is a potential unique physiological target for critical care. Further work into the high-frequency relationship between critical care and CVR is required.

Impact of Chronological Age and Biological Sex on Cerebrovascular Reactivity in Moderate/Severe Traumatic Brain Injury: A CAnadian High-Resolution Traumatic Brain Injury (CAHR-TBI) Study.

Impaired cerebrovascular reactivity has emerged as an important associate with poor long-term outcome after moderate/severe traumatic brain injury (TBI). However, our understanding of what drives or modulates the degree of impaired cerebrovascular function remains poor. Age and biological sex remain important modifiers of cerebrovascular function in health and disease, yet their impact on cerebrovascular reactivity after TBI remains unclear. The aim of this study was to explore subgroup responses based on age and biological sex on cerebral physiology. Data from 283 TBI patients from the CAnadian High Resolution TBI (CAHR-TBI) Research Collaborative were evaluated. Cerebrovascular reactivity was determined using high-frequency cerebral physiology for the derivation of three intracranial pressure (ICP)-based indices: 1) pressure reactivity index (PRx)-correlation between ICP and mean arterial pressure (MAP); 2) pulse amplitude index (PAx)-correlation between pulse amplitude of ICP (AMP) and MAP; and 3) RAC-correlation between AMP and cerebral perfusion pressure (CPP). Insult burden (% time above clinically defined thresholds) were calculated for these indices. These cerebral physiology indices were studied for their relationship with age via linear regression, age trichotomization (< 40, 40 - 60, > 60), and decades of age (< 30, 30-39, 40-49, 50-59, 60-69, > 69) schemes. Similarly, differences based on biological sex were assessed. A statistically significant positive linear correlation was found between PAx, RAC, and age. In corollary, a statistically significant relationship was found between increasing age on trichotomized and decades of age analysis with PAx and RAC measures. PRx failed to demonstrate such relationships to advancing age. There was no clear difference in cerebrovascular reactivity profiles between biological sex categories. These findings suggest that AMP-based cerebrovascular reactivity indices may be better positioned to detect impairment in TBI patients with advancing age. Further investigation into the utility of PAx and RAC is required, as they may prove useful for certain subgroups of patients.

Assessment of Cerebral Autoregulation Using Invasive and Noninvasive Methods of Intracranial Pressure Monitoring.

Pulse amplitude index (PAx), a descriptor of cerebrovascular reactivity, correlates the changes of the pulse amplitude of theintracranial pressure (ICP) waveform (AMP) with changes in mean arterial pressure (MAP). AMP relies on cerebrovascular compliance, which is modulated by the state of the cerebrovascular reactivity. PAx can aid in prognostication after acute brain injuries as a tool for the assessment of cerebral autoregulation and could potentially tailor individual management; however, invasive measurements are required for its calculation. Our aim was to evaluate the relationship between noninvasive PAx (nPAx) derived from a novel noninvasive device for ICP monitoring and PAx derived from gold standard invasive methods. We retrospectively analyzed invasiveICP (external ventricular drain) and non-invasiveICP (nICP), viamechanical extensometer (Brain4Care Corp.). Invasive and non-invasive ICP waveform morphology data wascollected in adult patients with brain injury with arterial blood pressure monitoring. The time series from all signals were first treated to remove movement artifacts. PAx and nPAx were calculated as the moving correlation coefficients of 10-s averages of AMP or non-invasiveAMP(nAMP) andMAP. AMP/nAMP was determined by calculating the fundamental frequency amplitude of the ICP/nICP signal over a 10-s window, updated every 10-s. We then evaluated the relationship between invasive PAx and noninvasive nPAx using the methods of repeated-measures analysis to generate an estimate of the correlation coefficient and its 95% confidence interval (CI). The agreement between the two methods was assessed using the Bland-Altman test. Twenty-four patients were identified. The median age was 53.5years (interquartile range 40-70), and intracranial hemorrhage (84%) was the most common etiology. Twenty-one (87.5%) patients underwent mechanical ventilation, and 60% were sedated with a median Glasgow Coma Scale score of 8 (7-15). Mean PAx was 0.0296 ± 0.331, and nPAx was 0.0171 ± 0.332. The correlation between PAx and nPAx was strong (R = 0.70, p < 0.0005, 95% CI 0.687-0.717). Bland-Altman analysis showed excellent agreement, with a bias of - 0.018 (95% CI - 0.026 to - 0.01) and a localized regression trend line that did not deviate from 0. PAx can be calculated by conventionaland noninvasive ICP monitoring in a statistically significant evaluation with strong agreement. Further study of the applications of this clinical tool is warranted, with the goal of early therapeutic intervention to improve neurologic outcomes following acute brain injuries.

Intracranial Pressure-Derived Cerebrovascular Reactivity Indices, Chronological Age, and Biological Sex in Traumatic Brain Injury: A Scoping Review.

To date, there has been limited literature exploring the association between age and sex with cerebrovascular reactivity (CVR) in moderate/severe traumatic brain injury (TBI). Given the known link between age, sex, and cerebrovascular function, knowledge of the impacts on continuously assessed CVR is critical for the development of future therapeutics. We conducted a scoping review of the literature for studies that had a direct statistical interrogation of the relationship between age, sex, and continuous intracranial pressure (ICP)-based indices of CVR in moderate/severe TBI. The ICP-based indices researched included: pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC. MEDLINE, BIOSIS, EMBASE, SCOPUS, Global Health, and the Cochrane library were searched from inception to June 2021 for relevant articles. A total of 10 original studies fulfilled our inclusion criteria. Nine of the articles documented a correlation between advanced age and worse CVR, with eight using PRx (2192 total patients), three using PAx (978 total patients), and one using RAC (358 total patients), p < 0.05; R ranging from 0.17 to 0.495 for all indices across all studies. Three articles (1256 total patients) displayed a correlation between biological sex and PRx, with females trending towards higher PRx values (p < 0.05) in the limited available literature. However, no literature exists comparing PAx or RAC with biological sex. Findings showed that aging was associated with impaired CVR. We observed a trend between female sex and worse PRx values, but the literature was limited and statistical significance was borderline. The identified studies were few in number, carried significant population heterogeneity, and utilized grand averaging of large epochs of physiology during statistical comparisons with age and biological sex. Because of the heterogeneous nature of TBI populations and limited focus on the effects of age and sex on outcomes in TBI, it is challenging to highlight the differences between the indices and patient age groups and sex. The largest study showing an association between PRx and age was done by Zeiler and colleagues, where 165 patients were studied noting that patients with a mean PRx value above zero had a mean age above 51.4 years versus a mean age of 41.4 years for those with a mean PRx value below zero (p = 0.0007). The largest study showing an association between PRx and sex was done by Czosnyka and colleagues, where 469 patients were studied noting that for patients <50 years of age, PRx was worse in females (0.11 ± 0.047) compared to males (0.044 ± 0.031), p < 0.05. The findings from these 10 studies provide preliminary data, but are insufficient to definitively characterize the impact of age and sex on CVR in moderate/severe TBI. Future work in the field should focus on the impact of age and sex on multi-modal cerebral physiological monitoring.

Association of Outcomes with Model-Based Indices of Cerebral Autoregulation After Pediatric Traumatic Brain Injury.

We investigated whether model-based indices of cerebral autoregulation (CA) are associated with outcomes after pediatric traumatic brain injury. This was a retrospective analysis of a prospective clinical database of 56 pediatric patients with traumatic brain injury undergoing intracranial pressure monitoring. CA indices were calculated, including pressure reactivity index (PRx), wavelet pressure reactivity index (wPRx), pulse amplitude index (PAx), and correlation coefficient between intracranial pressure pulse amplitude and cerebral perfusion pressure (RAC). Each CA index was used to compute optimal cerebral perfusion pressure (CPP). Time of CPP below lower limit of autoregulation (LLA) or above upper limit of autoregulation (ULA) were computed for each index. Demographic, physiologic, and neuroimaging data were collected. Primary outcome was determined using Pediatric Glasgow Outcome Scale Extended (GOSE-Peds) at 12months, with higher scores being suggestive of unfavorable outcome. Univariate and multiple linear regression with guided stepwise variable selection was used to find combinations of risk factors that can best explain the variability of GOSE-Peds scores, and the best fit model was applied to the age strata. We hypothesized that higher GOSE-Peds scores were associated with higher CA values and more time below LLA or above ULA for each index. At the univariate level, CPP, dose of intracranial hypertension, PRx, PAx, wPRx, RAC, percent time more than ULA derived for PAx, and percent time less than LLA derived for PRx, PAx, wPRx, and RAC were all associated with GOSE-Peds scores. The best subset model selection on all pediatric patients identified that when accounting for CPP, increased dose of intracranial hypertension and percent time less than LLA derived for wPRx were independently associated with higher GOSE-Peds scores. Age stratification of the best fit model identified that in children less than 2years of age or 8years of ageor more, percent time less than LLA derived for wPRx represented the sole independent predictor of higher GOSE-Peds scores when accounting for CPP and dose of intracranial hypertension. For children 2years or younger to less than 8years of age, dose of intracranial hypertension was identified as the sole independent predictor of higher GOSE-Peds scores when accounting for CPP and percent time less than LLA derived for wPRx. Increased dose of intracranial hypertension, PRx, wPRx, PAx, and RAC values and increased percentage time less than LLA based on PRx, wPRx, PAx, and RAC are associated with higher GOSE-Peds scores, suggestive of unfavorable outcome. Reducing intracranial hypertension and maintaining CPP more than LLA based on wPRx may improve outcomes and warrants prospective investigation.

Physiologic Characteristics of Hyperosmolar Therapy After Pediatric Traumatic Brain Injury.

All work was performed at the Barrow Neurological Institute at Phoenix Children's Hospital.Objective: Investigate injury severity, neuroimaging, physiology, and outcomes with bolus hyperosmolar therapy (HT) of 3% hypertonic saline or mannitol.Methods: Retrospective cohort analysis was performed. Physiologic variables included intracranial pressure (ICP), arterial blood pressure (ABP), and heart rate (HR). Volume-pressure compensation (PVC) indices included ICP pulse amplitude (AMP) and correlation of AMP and ICP (RAP). Cerebrovascular pressure reactivity (CVPR) indices included pressure reactivity index (PRx), pulse amplitude index (PAx), wavelet PRx (wPRx), and correlation of AMP and cerebral perfusion pressure (RAC). Heart rate variability (HRV) indices included heart rate standard deviation (HRsd), heart rate root mean square of successive differences (HRrmssd) and low-high frequency ratio (LHF). Outcome was assessed using Glasgow Outcomes Scale Extended Pediatrics, 12-months post-injury. Generalized estimating equations was applied to investigate associations of physiologic changes and pre-treatment indices with HT efficacy. Repeated measures analysis of variance was applied to investigate changes after HT without intracranial hypertension (ICH). Wilcoxon rank-sum was applied to investigate HT responsiveness with age, injury severity, neuroimaging, and outcomes.Results: Thirty children received bolus HT. ICH reduction after HT was associated with reduced ICP (p = 0.0064), ABP (p = 0.0126), PRx (p = 0.0063), increased HRsd (p = 0.0408), and decreased pretreatment RAC (p = 0.0115) and wPRx (p = 0.0072). HT-responsive patients were older and had improved outcomes (p = 0.0394). HT without ICH was associated with increased ICP (P < 0.0001) and ABP (P < 0.0001), increases in all HRV indices and decreases in all PVC indices.Conclusion: After pediatric TBI, efficacious HT is associated with decreased ICP and ABP, pre-treatment indices suggesting efficient CVPR, and potentially improved outcomes.

Usability of Noninvasive Counterparts of Traditional Autoregulation Indices in Traumatic Brain Injury.

The pressure reactivity index (PRx) and the pulse amplitude index (PAx) are invasively determined parameters that are commonly used to describe autoregulation following traumatic brain injury (TBI). Using a transcranial Doppler ultrasound (TCD) technique, it is possible to approximate cerebral arterial blood volume (CaBV) solely from cerebral blood flow velocities, and further, to calculate non-invasive markers of autoregulation. In this brief study, we aimed to investigate whether the estimation of relative CaBV with different models could describe the cerebrovascular reactivity of TBI patients. PRx, PAx and their non-invasive counterparts (nPRx and nPAx) were calculated retrospectively from data collected during the monitoring of TBI patients. CaBV, an essential parameter for the calculation of nPRx and nPAx, was determined with both a continuous flow forward (CFF) model-considering a non-pulsatile blood outflow from the brain-and a pulsatile flow forward (PFF) model, presuming a pulsatile outflow. We found that the estimated CaBV demonstrates good coherence with ICP and that nPRx and nPAx can describe cerebrovascular reactivity similarly to PRx and PAx. Continuous monitoring with TCD is difficult, so the usability of PRx and PAx is limited. However, they might become useful for clinicians in the near future owing to rapid advances in these technologies.

Multimodal Assessment of Cerebral Autoregulation and Autonomic Function After Pediatric Cerebral Arteriovenous Malformation Rupture.

Management after cerebral arteriovenous malformation (AVM) rupture aims toward preventing hemorrhagic expansion while maintaining cerebral perfusion to avoid secondary injury. We investigated associations of model-based indices of cerebral autoregulation (CA) and autonomic function (AF) with outcomes after pediatric cerebral AVM rupture. Multimodal neurologic monitoring data from the initial 3days after cerebral AVM rupture were retrospectively analyzed in children (< 18years). AF indices included standard deviation of heart rate (HRsd), root-mean-square of successive differences in heart rate (HRrmssd), low-high frequency ratio (LHF), and baroreflex sensitivity (BRS). CA indices include pressure reactivity index (PRx), wavelet pressure reactivity indices (wPRx and wPRx-thr), pulse amplitude index (PAx), and correlation coefficient between intracranial pressure pulse amplitude and cerebral perfusion pressure (RAC). Percent time of cerebral perfusion pressure (CPP) below lower limits of autoregulation (LLA) was also computed for each CA index. Primary outcomes were determined using Pediatric Glasgow Outcome Score Extended-Pediatrics (GOSE-PEDs) at 12months and acquired epilepsy. Association of biomarkers with outcomes was investigated using linear regression, Wilcoxon signed-rank, or Chi-square. Fourteen children were analyzed. Lower AF indices were associated with poor outcomes (BRS [p = 0.04], HRsd [p = 0.04], and HRrmssd [p = 0.00]; and acquired epilepsy (LHF [p = 0.027]). Higher CA indices were associated with poor outcomes (PRx [p = 0.00], wPRx [p = 0.00], and wPRx-thr [p = 0.01]), and acquired epilepsy (PRx [p = 0.02] and wPRx [p = 0.00]). Increased time below LLA was associated with poor outcome (percent time below LLA based on PRx [p = 0.00], PAx [p = 0.04], wPRx-thr [p = 0.03], and RAC [p = 0.01]; and acquired epilepsy (PRx [p = 0.00], PAx [p = 0.00], wPRx-thr [p = 0.03], and RAC [p = 0.01]). After pediatric cerebral AVM rupture, poor outcomes are associated with AF and CA when applying various neurophysiologic model-based indices. Prospective work is needed to assess these indices of CA and AF in clinical decision support.

Alternative continuous intracranial pressure-derived cerebrovascular reactivity metrics in traumatic brain injury: a scoping overview.

Pressure reactivity index (PRx) has emerged as a means to continuously monitor cerebrovascular reactivity in traumatic brain injury (TBI). However, other intracranial pressure (ICP)-based continuous metrics exist, and may have advantages over PRx. The goal of this study was to perform a scoping overview of the literature on non-PRx ICP-based continuous cerebrovascular reactivity metrics in adult TBI. We searched MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to December 2019. Using a two-stage filtering of title/abstract, and then full manuscript, we identified pertinent articles. Data was abstracted to tables and each technique summarized, including pulse amplitude index (PAx), correlation between pulse amplitude of ICP and cerebral perfusion pressure (RAC), PRx55-15, and low-resolution metrics LAx and L-PRx. A total of 23 articles met the inclusion criteria, with the vast majority being retrospective in nature and based out of European centers. Sixteen articles focused on high-resolution metrics PAx, RAC, and PRx55-15, with 6 articles focusing on LAx and L-PRx. PAx may have a role in low ICP situations, where it appears to perform superior to PRx. RAC displays similar behavior to PRx, with a trend to stronger associations with favorable/unfavorable outcome at 6months, and stronger parabolic relationship with CPP. PRx55-15 provides a focused assessment on the vasogenic frequency range associated with cerebral autoregulation, with preliminary data supporting a strong association with outcome in TBI. LAx and L-PRx display varying associations with 6-month outcome in TBI, depending on the window length of calculation, with shorter windows demonstrating stronger correlations with classical PRx. Non-PRx continuous ICP-based cerebrovascular reactivity metrics can be split into high-resolution and low-resolution measures. High-resolution indices include PAx, RAC, and PRx55-15, while low-resolution indices include L-PRx and LAx. The true role for these metrics beyond classic PRx remains unclear. Each displays situations where it may prove superior over PRx, given limitations with this currently widely accepted measure. Much future investigation into each of these alternative metrics is required prior to adoption into the clinical monitoring armamentarium in adult TBI.

Relationship between Measures of Cerebrovascular Reactivity and Intracranial Lesion Progression in Acute Traumatic Brain Injury Patients: A CENTER-TBI Study.

Failure of cerebral autoregulation has been linked to unfavorable outcome after traumatic brain injury (TBI). Preliminary evidence from a small, retrospective, single-center analysis suggests that autoregulatory dysfunction may be associated with traumatic lesion expansion, particularly for pericontusional edema. The goal of this study was to further explore these associations using prospective, multi-center data from the Collaborative European Neurotrauma Effectiveness Research in TBI (CENTER-TBI) and to further explore the relationship between autoregulatory failure, lesion progression, and patient outcome. A total of 88 subjects from the CENTER-TBI High Resolution ICU Sub-Study cohort were included. All patients had an admission computed tomography (CT) scan and early repeat scan available, as well as high-frequency neurophysiological recordings covering the between-scan interval. Using a novel, semiautomated approach at lesion segmentation, we calculated absolute changes in volume of contusion core, pericontusional edema, and extra-axial hemorrhage between the imaging studies. We then evaluated associations between cerebrovascular reactivity metrics and radiological lesion progression using mixed-model regression. Analyses were adjusted for baseline covariates and non-neurophysiological factors associated with lesion growth using multi-variate methods. Impairment in cerebrovascular reactivity was significantly associated with progression of pericontusional edema and, to a lesser degree, intraparenchymal hemorrhage. In contrast, there were no significant associations with extra-axial hemorrhage. The strongest relationships were observed between RAC-based metrics and edema formation. Pulse amplitude index showed weaker, but consistent, associations with contusion growth. Cerebrovascular reactivity metrics remained strongly associated with lesion progression after taking into account contributions from non-neurophysiological factors and mean cerebral perfusion pressure. Total hemorrhagic core and edema volumes on repeat CT were significantly larger in patients who were deceased at 6 months, and the amount of edema was greater in patients with an unfavourable outcome (Glasgow Outcome Scale-Extended 1-4). Our study suggests associations between autoregulatory failure, traumatic edema progression, and poor outcome. This is in keeping with findings from a single-center retrospective analysis, providing multi-center prospective data to support those results.

Validation of non-invasive cerebrovascular pressure reactivity and pulse amplitude reactivity indices in traumatic brain injury

BackgroundTwo transcranial Doppler (TCD) estimators of cerebral arterial blood volume (CaBV) coexist: continuous outflow of arterial blood outside the cranium through a low-pulsatile venous system (continuous flow forward, CFF) and pulsatile outflow through regulating arterioles (pulsatile flow forward, PFF). We calculated non-invasive equivalents of the pressure reactivity index (PRx) and the pulse amplitude index PAx with slow waves of mean CaBV and its pulse amplitude.MethodsAbout 273 individual TBI patients were retrospectively reviewed. PRx is the correlation coefficient between 30 samples of 10-second averages of ICP and mean ABP. PAx is the correlation coefficient between 30 samples of 10-second averages of the amplitude of ICP (AMP, derived from Fourier analysis of the raw full waveform ICP tracing) and mean ABP. nPRx is calculated with CaBV instead of ICP and nPAx with the pulse amplitude of CaBV instead of AMP (calculated using both the CFF and PFF models). All reactivity indices were additionally compared with Glasgow Outcome Score (GOS) to verify potential outcome-predictive strength.ResultsWhen correlated, slow waves of ICP demonstrated good coherence between slow waves in CaBV (>0.75); slow waves of AMP showed good coherence with slow waves of the pulse amplitude of CaBV (>0.67) in both the CFF and PFF models. nPRx was moderately correlated with PRx (R = 0.42 for CFF and R = 0.38 for PFF; p < 0.0001). nPAx correlated with PAx with slightly better strength (R = 0.56 for CFF and R = 0.41 for PFF; p < 0.0001). nPAx_CFF showed the strongest association with outcomes.ConclusionsNon-invasive estimators (nPRx and nPAx) are associated with their invasive counterparts and can provide meaningful associations with outcome after TBI. The CFF model is slightly superior to the PFF model.

Relationship Between Measures of Cerebrovascular Reactivity and Intracranial Lesion Progression in Acute TBI Patients: an Exploratory Analysis

BackgroundFailure of cerebral autoregulation and progression of intracranial lesion have both been shown to contribute to poor outcome in patients with acute traumatic brain injury (TBI), but the interplay between the two phenomena has not been investigated. Preliminary evidence leads us to hypothesize that brain tissue adjacent to primary injury foci may be more vulnerable to large fluctuations in blood flow in the absence of intact autoregulatory mechanisms. The goal of this study was therefore to assess the influence of cerebrovascular reactivity measures on radiological lesion expansion in a cohort of patients with acute TBI.MethodsWe conducted a retrospective cohort analysis on 50 TBI patients who had undergone high-frequency multimodal intracranial monitoring and for which at least two brain computed tomography (CT) scans had been performed in the acute phase of injury. We first performed univariate analyses on the full cohort to identify non-neurophysiological factors (i.e., initial lesion volume, timing of scan, coagulopathy) associated with traumatic lesion growth in this population. In a subset analysis of 23 patients who had intracranial recording data covering the period between the initial and repeat CT scan, we then correlated changes in serial volumetric lesion measurements with cerebrovascular reactivity metrics derived from the pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC (correlation coefficient between the pulse amplitude of intracranial pressure and cerebral perfusion pressure). Using multivariate methods, these results were subsequently adjusted for the non-neurophysiological confounders identified in the univariate analyses.ResultsWe observed significant positive linear associations between the degree of cerebrovascular reactivity impairment and progression of pericontusional edema. The strongest correlations were observed between edema progression and the following indices of cerebrovascular reactivity between sequential scans: % time PRx > 0.25 (r = 0.69, p = 0.002) and % time PAx > 0.25 (r = 0.64, p = 0.006). These associations remained significant after adjusting for initial lesion volume and mean cerebral perfusion pressure. In contrast, progression of the hemorrhagic core and extra-axial hemorrhage volume did not appear to be strongly influenced by autoregulatory status.ConclusionsOur preliminary findings suggest a possible link between autoregulatory failure and traumatic edema progression, which warrants re-evaluation in larger-scale prospective studies.

Validation of Intracranial Pressure-Derived Cerebrovascular Reactivity Indices against the Lower Limit of Autoregulation, Part II: Experimental Model of Arterial Hypotension.

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.

Intracranial and Extracranial Injury Burden as Drivers of Impaired Cerebrovascular Reactivity in Traumatic Brain Injury.

Impaired cerebrovascular reactivity has been associated with outcome following traumatic brain injury (TBI), but it is unknown how it is affected by trauma severity. Thus, we aimed to explore the relationship between intracranial (IC) and extracranial (EC) injury burden and cerebrovascular reactivity in TBI patients. We retrospectively included critically ill TBI patients. IC injury burden included detailed lesion and computerized tomography (CT) scoring (i.e., Marshall, Rotterdam, Helsinki, and Stockholm Scores) on admission. EC injury burden was characterized using the injury severity score (ISS) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC were used to assess autoregulation/cerebrovascular reactivity. We used univariate and multi-variate logistic regression techniques to explore relationships between IC and EC injury burden and autoregulation indices. A total of 358 patients were assessed. ISS and all IC CT scoring systems were poor predictors of impaired cerebrovascular reactivity. Only subdural hematomas and thickness of subarachnoid hemorrhage (SAH; p < 0.05, respectively) were consistently associated with dysfunctional cerebrovascular reactivity. High age (p < 0.01 for all) and admission APACHE II scores (p < 0.05 for all) were the two variables most strongly associated with abnormal cerebrovascular reactivity. In summary, diffuse IC injury markers (thickness of SAH and the presence of a subdural hematoma) and APACHE II were most associated with dysfunction in cerebrovascular reactivity after TBI. Standard CT scoring systems and evidence of macroscopic parenchymal damage are poor predictors, implicating potentially both microscopic injury patterns and host response as drivers of dysfunctional cerebrovascular reactivity. Age remains a major variable associated with cerebrovascular reactivity.

A Description of a New Continuous Physiological Index in Traumatic Brain Injury Using the Correlation between Pulse Amplitude of Intracranial Pressure and Cerebral Perfusion Pressure.

To describe a new continuous index of physiologic measurement in a traumatic brain injury (TBI) population, the moving correlation coefficient between intracranial pressure (ICP) pulse amplitude (AMP) and cerebral perfusion pressure (CPP), which we refer to as RAC. We use patient examples of sustained intracranial hypertension, systemic arterial hypotension, and plateau waves, as well as the retrospective analysis of 358 non-decompressive craniectomy (DC) TBI patients with high-frequency ICP and arterial blood pressure data, to explore the relationships of this new index, RAC, with AMP, ICP, CPP, RAP (correlation coefficient between AMP and ICP), pressure reactivity index (PRx), and pulse amplitude index (PAx). We compared the RAC-CPP relationship to that observed between CPP and both PRx and PAx. RAC displays temporal responsiveness to sustained increased ICP, arterial hypotension, and plateau waves, with positive values found during episodes of high ICP and low CPP. Analysis of AMP versus CPP and AMP versus ICP relationships in data from the entire non-DC cohort show lower breakpoints for AMP/CPP at CPP = 40 mm Hg and upper breakpoints for AMP/ICP at ICP = 50-60 mm Hg. RAC trends to positive values with increasing ICP, particularly with ICP values above the peak in AMP (ICP >50 mm Hg), though its interpretation requires concomitant interpretation of AMP, RAP, and PRx/PAx to determine contributions of compensatory reserve and cerebrovascular responsiveness to the changes observed in RAC. There is a parabolic relationship between RAC versus CPP, with trends toward positive RAC values near (and beyond) limits for low and high CPPs, suggesting that RAC may be used in the determination of optimum CPP. RAC appears to carry information regarding both cerebrovascular responsiveness and cerebral compensatory reserve. This contributes to RAC's uniqueness and complex interpretation. Further prospective, clinical studies of RAC in CPP optimum estimation and outcome prediction in TBI are required.

Critical Thresholds of Intracranial Pressure-Derived Continuous Cerebrovascular Reactivity Indices for Outcome Prediction in Noncraniectomized Patients with Traumatic Brain Injury.

The aim of the study was to compare intracranial pressure (ICP)-derived cerebrovascular reactivity indices in their ability to predict six-month outcome, and to determine/compare critical thresholds related to outcome for each index in adult noncraniectomized traumatic brain injury (TBI). Using a retrospective cohort of nondecompressive craniectomy (non-DC) patients with TBI, we performed univariate and multi-variate binary logistic regression outcome analysis of: pressure reactivity index (PRx), pulse amplitude index (PAx), and a newly described index (RAC) calculated as the regression coefficient between ICP waveform amplitude and cerebral perfusion pressure (CPP). Finally, we performed sequential chi-square threshold analysis for each index as it related to six-month binary outcomes. Outcome was assessed via dichotomized Glasgow Outcome Scores (GOS): (A) favorable (GOS 4 or 5) versus unfavorable (GOS 3 or less), (B) alive versus dead. There were 358 non-DC patients with TBI included in all aspects of the analysis. In an analysis of the entire recording period for all patients using univariate binary logistic regression, the areas under the curves (AUCs) for favorable versus unfavorable outcome were: PRx (0.573, p < 0.0001), PAx (0.606, p < 0.0001), and RAC (0.655, p < 0.0001). Similarly, the AUCs for alive versus dead outcome were: PRx (0.651, p < 0.0001), PAx (0.705, p < 0.0001), and RAC (0.722, p < 0.0001). RAC displayed superior AUC statistics compared with PRx and PAx, using both univariate and multi-variate regression. RAC displayed more stable critical thresholds related to six-month outcomes. Thresholds for both favorable versus unfavorable and alive versus dead outcomes for PRx, PAx, and RAC across the entire recording period were: +0.35 and +0.35, 0 and +0.25, -0.10 and -0.05, respectively. In non-DC patients with TBI, RAC appears to be superior to PRx and PAx in six-month outcome prediction, using both univariate and multi-variate logistic regression. Further, RAC displayed more stable critical thresholds associated with binary outcomes at six months. Further analysis of RAC in TBI is required.

Critical Thresholds of ICP Derived Continuous Cerebrovascular Reactivity Indices for outcome prediction in Non-Craniectomized TBI Patients: PRx, PAx and RAC.

To compare ICP derived cerebrovascular reactivity indices in their ability to predict 6-month outcome, and to determine/compare critical thresholds related to outcome for each index, in adult non-craniectomized traumatic brain injury (TBI). Using a retrospective cohort of non-decompressive craniectomy (non-DC) TBI patients, we performed univariate and multivariate binary logistic regression outcome analysis of: pressure reactivity index (PRx), pulse amplitude index (PAx) and a newly described index calculated as the Regression coefficient between intracranial pressure (ICP) waveform Amplitude and Cerebral perfusion pressure RAC (CPP). Finally, we performed sequential chi-square threshold analysis for each index as they related to 6-month binary outcomes. Outcome was assessed via dichotomized Glasgow Outcome Scores (GOS): A. Favourable (GOS 4 or 5) vs. Unfavourable (GOS 3 or less), B. Alive vs. Dead. 358 non-DC TBI patients were included in all aspects of the analysis. In an analysis of the entire recordin...