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Impact of Age and Biological Sex on Cerebrovascular Reactivity in Adult Moderate/Severe Traumatic Brain Injury: An Exploratory Analysis.

ABSTRACT: Age and biological sex are two potential important modifiers of cerebrovascular reactivity post-traumatic brain injury (TBI) requiring close evaluation for potential subgroup responses. The goal of this study was to provide a preliminary exploratory analysis of the impact of age and biological sex on measures of cerebrovascular function in moderate/severe TBI. Forty-nine patients from the prospectively maintained TBI database at the University of Manitoba with archived high-frequency digital cerebral physiology were evaluated. Cerebrovascular reactivity indices were derived as follows: PRx (correlation between intracranial pressure [ICP] and mean arterial pressure [MAP]), PAx (correlation between pulse amplitude of ICP [AMP] and MAP), and RAC (correlation between AMP and cerebral perfusion pressure [CPP]). Time above clinically significant thresholds for each index was calculated over different periods of the acute intensive care unit stay. The association between PRx, PAx, and RAC measures with age was assessed using linear regression, and an age trichotomization scheme (<40, 40-60, >60) using Kruskal-Wallis testing. Similarly, association with biological sex was tested using Mann-Whitney U testing. Biological sex did not demonstrate an impact on any measures of cerebrovascular reactivity. Linear regression between age and PAx and RAC demonstrated a statistically significant positive linear relationship. Median PAx and RAC measures between trichotomized age categories demonstrated statistically significant increases with advancing age. The PRx failed to demonstrate any statistically significant relationship with age in this cohort, suggesting that in elderly patients with controlled ICP, PAx and RAC may be better metrics for detecting impaired cerebrovascular reactivity. Biological sex appears to not be associated with differences in cerebrovascular reactivity in this cohort. The PRx performed the worst in detecting impaired cerebrovascular reactivity in those with advanced age, where PAx and RAC appear to have excelled. Future work is required to validate these findings and explore the utility of different cerebrovascular reactivity indices.

SUBMITTER: Batson C

PROVIDER: S-EPMC8655816 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:BackgroundThe aim of this study is to evaluate the impact of commonly administered sedatives (Propofol, Alfentanil, Fentanyl, and Midazolam) and vasopressor (Dobutamine, Ephedrine, Noradrenaline and Vasopressin) agents on cerebrovascular reactivity in moderate/severe TBI patients. Cerebrovascular reactivity, as a surrogate for cerebral autoregulation was assessed using the long pressure reactivity index (LPRx). We evaluated the data in two phases, first we assessed the minute-by-minute data relationships between different dosing amounts of continuous infusion agents and physiological variables using boxplots, multiple linear regression and ANOVA. Next, we assessed the relationship between continuous/bolus infusion agents and physiological variables, assessing pre-/post- dose of medication change in physiology using a Wilcoxon signed-ranked test. Finally, we evaluated sub-groups of data for each individual dose change per medication, focusing on key physiological thresholds and demographics.ResultsOf the 475 patients with an average stay of 10 days resulting in over 3000 days of recorded information 367 (77.3%) were male with a median Glasgow coma score of 7 (4-9). The results of this retrospective observational study confirmed that the infusion of most administered agents do not impact cerebrovascular reactivity, which is confirmed by the multiple linear regression components having p value > 0.05. Incremental dose changes or bolus doses in these medications in general do not lead to significant changes in cerebrovascular reactivity (confirm by Wilcoxon signed-ranked p value > 0.05 for nearly all assessed relationships). Within the sub-group analysis that separated the data based on LPRx pre-dose, a significance between pre-/post-drug change in LPRx was seen, however this may be more of a result from patient state than drug impact.ConclusionsOverall, this study indicates that commonly administered agents with incremental dosing changes have no clinically significant influence on cerebrovascular reactivity in TBI (nor do they impair cerebrovascular reactivity). Though further investigation in a larger and more diverse TBI patient population is required.

Project description:BackgroundIntravenous hypertonic saline is utilized commonly in critical care for treatment of acute or refractory elevations of intracranial pressure (ICP) in traumatic brain injury (TBI) patients. Though there is a clear understanding of the general physiological effects of a hypertonic saline solution over long periods of time, smaller epoch effects of hypertonic saline (HTS) have not been thoroughly analyzed. The aim of this study was to perform a direct evaluation of the high-frequency response of HTS on the cerebrovascular physiological responses in TBI.MethodsWe retrospectively reviewed our prospectively maintained adult TBI database for those with archived high-frequency cerebral physiology and available HTS treatment information. We evaluated different epochs of physiology around HTS bolus dosing, comparing pre- with post-HTS. We assessed for changes in slow fluctuations in ICP, pulse amplitude of ICP (AMP), cerebral perfusion pressure (CPP), mean arterial pressure (MAP), cerebrovascular reactivity (as measured through pressure reactivity index (PRx)), and cerebral compensatory reserve (correlation (R) between AMP (A) and ICP (P)). Comparisons of mean measures and percentage time above clinically relevant thresholds for the physiological parameters were compared pre- and post-HTS using descriptive statistics and Mann-Whitney U testing. We assessed for subgroups of physiological responses using latent profile analysis (LPA).ResultsFifteen patients underwent 69 distinct bolus infusions of hypertonic saline. Apart from the well-documented decrease in ICP, there was also a reduction in AMP. The analysis of cerebrovascular reactivity response to HTS solution had two main effects. For patients with grossly impaired cerebrovascular reactivity pre-HTS (PRx > + 0.30), HTS bolus led to improved reactivity. However, for those with intact cerebrovascular reactivity pre-HTS (PRx < 0), HTS bolus demonstrated a trend towards more impaired reactivity. This indicates that HTS has different impacts, dependent on pre-bolus cerebrovascular status. There was no significant change in metrics of cerebral compensatory reserve. LPA failed to demonstrate any subgroups of physiological responses to HTS administration.ConclusionsThe direct decrease in ICP and AMP confirms that a bolus dose of a HTS solution is an effective therapeutic agent for intracranial hypertension. However, in patients with intact autoregulation, hypertonic saline may impair cerebral hemodynamics. These findings regarding cerebrovascular reactivity remain preliminary and require further investigation.

Project description:BACKGROUND:Cerebral injury may alter the autoregulation of cerebral blood flow. One index for describing cerebrovascular state is the pressure reactivity (PR). Little is known of whether PR is associated with measures of brain metabolism and indicators of ischemia and cell damage. The aim of this investigation was to explore whether increased interstitial levels of glycerol, a marker of cell membrane damage, are associated with PR, and if prostacyclin, a membrane stabilizer and regulator of the microcirculation, may affect this association in a beneficial way. MATERIALS AND METHODS:Patients suffering severe traumatic brain injury (sTBI) were treated according to an intracranial pressure (ICP)-targeted therapy based on the Lund concept and randomized to an add-on treatment with prostacyclin or placebo. Inclusion criteria were verified blunt head trauma, Glasgow Coma Score???8, age 15-70 years, and a first measured cerebral perfusion pressure of???10 mmHg. Multimodal monitoring was applied. A brain microdialysis catheter was placed on the worst affected side, close to the penumbra zone. Mean (glycerolmean) and maximal glycerol (glycerolmax) during the 96-h sampling period were calculated. The mean PR was calculated as the ICP/mean arterial pressure (MAP) regression coefficient based on hourly mean ICP and MAP during the first 96 h. RESULTS:Of the 48 included patients, 45 had valid glycerol and PR measurements available. PR was higher in the placebo group as compared to the prostacyclin group (p?=?0.0164). There was a positive correlation between PR and the glycerolmean (??=?0.503, p?=?0.01) and glycerolmax (??=?0.490, p?=?0.015) levels in the placebo group only. CONCLUSIONS:PR is correlated to the glycerol level in patients suffering from sTBI, a relationship that is not seen in the group treated with prostacyclin. Glycerol has been associated with membrane degradation and may support glycerol as a biomarker for vascular endothelial breakdown. Such a breakdown may impair the regulation of cerebrovascular PR.

Project description:BackgroundImpaired cerebrovascular reactivity in adult traumatic brain injury (TBI) is known to be associated with poor outcome. However, there has yet to be an analysis of the association between the comprehensively assessed intracranial hypertension therapeutic intensity level (TIL) and cerebrovascular reactivity.MethodsUsing the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit (ICU) cohort, we derived pressure reactivity index (PRx) as the moving correlation coefficient between slow-wave in ICP and mean arterial pressure, updated every minute. Mean daily PRx, and daily % time above PRx of 0 were calculated for the first 7 days of injury and ICU stay. This data was linked with the daily TIL-Intermediate scores, including total and individual treatment sub-scores. Daily mean PRx variable values were compared for each TIL treatment score via mean, standard deviation, and the Mann U test (Bonferroni correction for multiple comparisons). General fixed effects and mixed effects models for total TIL versus PRx were created to display the relation between TIL and cerebrovascular reactivity.ResultsA total of 249 patients with 1230 ICU days of high frequency physiology matched with daily TIL, were assessed. Total TIL was unrelated to daily PRx. Most TIL sub-scores failed to display a significant relationship with the PRx variables. Mild hyperventilation (p < 0.0001), mild hypothermia (p = 0.0001), high levels of sedation for ICP control (p = 0.0001), and use vasopressors for CPP management (p < 0.0001) were found to be associated with only a modest decrease in mean daily PRx or % time with PRx above 0.ConclusionsCerebrovascular reactivity remains relatively independent of intracranial hypertension therapeutic intensity, suggesting inadequacy of current TBI therapies in modulating impaired autoregulation. These findings support the need for investigation into the molecular mechanisms involved, or individualized physiologic targets (ICP, CPP, or Co2) in order to treat dysautoregulation actively.

Project description:The impact of vasopressor and sedative drugs on cerebrovascular reactivity in traumatic brain injury (TBI) remains unclear. The aim of this study was to evaluate the impact of changes of doses of commonly administered sedation (i.e., propofol, fentanyl, and ketamine) and vasopressor agents (i.e., norepinephrine [NE], phenylephrine [PE], and vasopressin[VSP]) on cerebrovascular reactivity and compensatory reserve in patients with moderate/severe TBI. Using the Winnipeg Acute TBI Database, we identified 38 patients with more than 1000 distinct changes of infusion rates and more than 500 h of paired drug infusion/physiology data. Cerebrovascular reactivity was assessed using pressure reactivity index (PRx) and cerebral compensatory reserve was assessed using RAP (the correlation [R] between pulse amplitude of intracranial pressure [ICP; A] and ICP [P]). We evaluated the data in two phases. First, we assessed the relationship between mean hourly dose of medication and its relation to both mean hourly index values, and time spent above a given index threshold. Second, we evaluated time-series data for each individual dose change per medication, assessing for a statistically significant change in PRx and RAP metrics. The results of the analysis confirmed that, overall, the mean hourly dose of sedative (propofol, fentanyl, and ketamine) and vasopressor (NE, PE, and VSP) agents does not impact hourly cerebrovascular reactivity or compensatory reserve measures. Similarly, incremental dose changes in these medications in general do not lead to significant changes in cerebrovascular reactivity or compensatory reserve. For propofol with incremental dose increases, in situations where PRx is intact (i.e., PRx <0 prior), a statistically significant increase in PRx was seen. However, this may not indicate deteriorating cerebrovascular reactivity as the final PRx (∼0.05) may still be considered to be intact cerebrovascular reactivity. As such, this finding with regards to propofol remains "weak." This study indicates that commonly administered sedative and vasopressor agents with incremental dosing changes have no clinically significant influence on cerebrovascular reactivity or compensatory reserve in TBI. These results should be considered preliminary, requiring further investigation.

Project description:Pressure reactivity index (PRx) and brain tissue oxygen (PbtO2) are associated with outcome in traumatic brain injury (TBI). This study explores the relationship between PRx and PbtO2 in adult moderate/severe TBI. Using the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) high resolution intensive care unit (ICU) sub-study cohort, we evaluated those patients with archived high-frequency digital intraparenchymal intracranial pressure (ICP) and PbtO2 monitoring data of, a minimum of 6 h in duration, and the presence of a 6 month Glasgow Outcome Scale -Extended (GOSE) score. Digital physiological signals were processed for ICP, PbtO2, and PRx, with the % time above/below defined thresholds determined. The duration of ICP, PbtO2, and PRx derangements was characterized. Associations with dichotomized 6-month GOSE (alive/dead, and favorable/unfavorable outcome; ≤ 4 = unfavorable), were assessed. A total of 43 patients were included. Severely impaired cerebrovascular reactivity was seen during elevated ICP and low PbtO2 episodes. However, most of the acute ICU physiological derangements were impaired cerebrovascular reactivity, not ICP elevations or low PbtO2 episodes. Low PbtO2 without PRx impairment was rarely seen. % time spent above PRx threshold was associated with mortality at 6 months for thresholds of 0 (area under the curve [AUC] 0.734, p = 0.003), > +0.25 (AUC 0.747, p = 0.002) and > +0.35 (AUC 0.745, p = 0.002). Similar relationships were not seen for % time with ICP >20 mm Hg, and PbtO2 < 20 mm Hg in this cohort. Extreme impairment in cerebrovascular reactivity is seen during concurrent episodes of elevated ICP and low PbtO2. However, the majority of the deranged cerebral physiology seen during the acute ICU phase is impairment in cerebrovascular reactivity, with most impairment occurring in the presence of normal PbtO2 levels. Measures of cerebrovascular reactivity appear to display the most consistent associations with global outcome in TBI, compared with ICP and PbtO2.

Project description:ObjectivesTo examine cerebrovascular pressure reactivity index (PRx) in a large cohort of children with severe traumatic brain injury (sTBI) in association with physiologic variables and outcome.DesignRetrospective observational cohort study.SettingRed Cross War Memorial Children's Hospital in Cape Town, South Africa.PatientsPediatric (≤ 14 yr old) sTBI patients with intracranial pressure (ICP) monitoring (postresuscitation Glasgow Coma Score [Glasgow Coma Scale (GCS)] of ≤ 8).Measurements and main resultsData were analyzed from ICM+ files sampled at 100Hz. PRx (a mathematical indicator of pressure reactivity) was calculated as a moving correlation coefficient between ICP and mean arterial pressure (MAP) as previously described. Associations between PRx, age, GCS, ICP, MAP, and cerebral perfusion pressure (CPP) were examined with summary measures and correlation analysis using high-frequency data. Associations between PRx and mortality/outcome were examined with multivariable logistic regression analysis and the prognostic ability of PRx with receiver operating characteristic (ROCs) curves. The dataset included over 1.7 million minutes (28,634 hr) of MAP and ICP data in 196 children. The series mortality was 10.7% (21/196), and unfavorable outcome 29.6% (58/196). PRx had a moderate positive correlation with ICP ( r = 0.44; p < 0.001), a moderate negative correlation with CPP ( r = -0.43; p < 0.001), and a weak negative correlation with MAP ( r = -0.21; p = 0.004). PRx was consistently higher in patients with poor outcome and had a strong, independent association with mortality (ROC area under the curve = 0.91). A PRx threshold of 0.25 showed the best predictive ability for mortality.ConclusionsThis is the largest cohort of children with PRx analysis of cerebrovascular reactivity to date. PRx had a strong association with outcome that was independent of ICP, CPP, GCS, and age. The data suggest that impaired autoregulation is an independent factor associated with poor outcome and may be useful in directing clinical care.

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Impact of Age and Biological Sex on Cerebrovascular Reactivity in Adult Moderate/Severe Traumatic Brain Injury: An Exploratory Analysis.

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