Does Targeting CPP at CPPopt Actually Improve Cerebrovascular Reactivity? A Secondary Analysis of the COGiTATE Randomized Controlled Trial

The status of autoregulation is an important prognostic factor in traumatic brain injury (TBI), and is important to consider in the management of TBI patients. Pressure reactivity index (PRx) is a measure of autoregulation that has been thoroughly studied, but little is known about its variation in different subtypes of TBI. In this study, we examined the impact of PRx and cerebral perfusion pressure (CPP) on outcome in different TBI subtypes. 107 patients were retrospectively studied. Data on PRx, CPP, and outcome were collected from our database. The first CT scan was classified according to the Marshall classification system. Patients were assigned to "diffuse" (Marshall class: diffuse-1, diffuse-2, and diffuse-3) or "focal" (Marshall class: diffuse-4, evacuated mass lesion, and non-evacuated mass lesion) groups. 2 × 2 tables were constructed calculating the proportions of favorable/unfavorable outcome at different combinations of PRx and CPP. Low PRx was significantly associated with favorable outcome in the combined group (p = 0.002) and the diffuse group (p = 0.04), but not in the focal group (p = 0.06). In the focal group higher CPP values were associated with worse outcome (p = 0.02). In diffuse injury patients with disturbed autoregulation (PRx >0.1), CPP >70 mmHg was associated with better outcome (p = 0.03). TBI patients with diffuse injury may differ from those with mass lesions. In the latter higher levels of CPP may be harmful, possibly due to BBB disruption. In TBI patients with diffuse injury and disturbed autoregulation higher levels of CPP may be beneficial.

Targets for treatment of raised intracranial pressure or decreased cerebral perfusion pressure in pediatric neurocritical care are not well defined. Current pediatric guidelines, based on traumatic brain injury, suggest an intracranial pressure target of less than 20 mm Hg and cerebral perfusion pressure minimum of 40-50 mm Hg, with possible age dependence of cerebral perfusion pressure. We sought to define intracranial pressure and cerebral perfusion pressure thresholds associated with inhospital mortality across a large single-center pediatric neurocritical care cohort. Retrospective chart review. PICU, single quaternary-care center. Individuals receiving intracranial pressure monitoring from January 2012 to December 2016. None. Intracranial pressure and cerebral perfusion pressure measurements from 262 neurocritical care patients (87 traumatic brain injury and 175 nontraumatic brain injury; 63% male; 8.3 ± 5.8 yr; mortality 11.1%). Mean intracranial pressure and cerebral perfusion pressure had area under the receiver operating characteristic curves of 0.75 and 0.64, respectively, for association of inhospital mortality. Cerebral perfusion pressure cut points increased with age (< 2 yr = 47, 2 to < 8 yr = 58 mm Hg, ≥ 8 yr = 73 mm Hg). In the traumatic brain injury subset, mean intracranial pressure and cerebral perfusion pressure had area under the receiver operating characteristic curves of 0.70 and 0.78, respectively, for association of inhospital mortality. Traumatic brain injury cerebral perfusion pressure cut points increased with age (< 2 yr = 45, 2 to < 8 yr = 57, ≥ 8 yr = 68 mm Hg). Mean intracranial pressure greater than 15 mm Hg, male sex, and traumatic brain injury status were independently associated with inhospital mortality (odds ratio, 14.23 [5.55-36.46], 2.77 [1.04-7.39], and 2.57 [1.03-6.38], respectively; all p < 0.05). Mean cerebral perfusion pressure less than 67 mm Hg and traumatic brain injury status were independently associated with inhospital mortality (odds ratio, 5.16 [2.05-12.98] and 3.71 [1.55-8.91], respectively; both p < 0.01). In the nontraumatic brain injury subset, mean intracranial pressure had an area under the receiver operating characteristic curve 0.77 with an intracranial pressure cut point of 15 mm Hg, whereas mean cerebral perfusion pressure was not predictive of inhospital mortality. We identified mean intracranial pressure thresholds, utilizing receiver operating characteristic and regression analyses, associated with inhospital mortality that is below current guidelines-based treatment targets in both traumatic brain injury and nontraumatic brain injury patients, and age-dependent cerebral perfusion pressure thresholds associated with inhospital mortality that were above current guidelines-based targets in traumatic brain injury patients. Further study is warranted to identify data-driven intracranial pressure and cerebral perfusion pressure targets in children undergoing intracranial pressure monitoring, whether for traumatic brain injury or other indications.

IntroductionCurrent guidelines for spontaneous intracerebral hemorrhage (ICH) recommend maintaining cerebral perfusion pressure (CPP) between 50 and 70 mmHg, depending on the state of autoregulation. We continuously assessed dynamic cerebral autoregulation and the possibility of determination of an optimal CPP (CPPopt) in ICH patients. Associations between autoregulation, CPPopt and functional outcome were explored.MethodsIntracranial pressure (ICP), mean arterial pressure (MAP) and CPP were continuously recorded in 55 patients, with 38 patients included in the analysis. The pressure reactivity index (PRx) was calculated as moving correlation between MAP and ICP. CPPopt was defined as the CPP associated with the lowest PRx values. CPPopt was calculated using hourly updated of 4 hour windows. The modified Rankin Scale (mRS) was assessed at 3 months and associations between PRx, CPPopt and outcomes were explored using Pearson correlation and Fisher’s exact test. Multivariate stepwise logistic regression models were calculated including standard outcome predictors along with percentage of time with PRx >0.2 and percentage of time within the CPPopt range.ResultsAn overall PRx indicating impairment of pressure reactivity was found in 47% of patients (n = 18). The mean PRx and the time spent with a PRx > 0.2 significantly correlated with mRS at 3 months (r = 0.50, P = 0.002; r = 0.46, P = 0.004). CPPopt was calculable during 57% of the monitoring time. The median CPP was 78 mmHg, the median CPPopt 83 mmHg. Mortality was lowest in the group of patients with a CPP close to their CPPopt. However, for none of the CPPopt variables a significant association to outcome was found. The percentage of time with impaired autoregulation and hemorrhage volume were independent predictors for acceptable outcome (mRS 1 to 4) at three months.ConclusionsFailure of pressure reactivity seems common following severe ICH and is associated with unfavorable outcome. Real-time assessment of CPPopt is feasible in ICH and might provide a tool for an autoregulation-oriented CPP management. A larger trial is needed to explore if a CPPopt management results in better functional outcomes.

To the Editor, We read with interest the recent publication by Sorrentino et al. [1] entitled: ‘‘Critical Thresholds for Cerebrovascular Reactivity after Traumatic Brain Injury’’. The study is based on the hypothesis that bedside real-time calculation of the pressure-reactivity index (PRx) allows a continuous estimation of cerebral pressure autoregulation [1–3]. From measurements of hydrostatic pressure alone the authors define threshold levels for survival as well as favorable outcome in patients with severe traumatic brain lesions. Pressure autoregulation is present in many tissues but it is most pronounced in the brain and the kidney. The main ‘‘physiological purpose’’ of pressure autoregulation is probably to keep intracapillary hydrostatic pressure relatively constant [4]. Changes in precapillary resistance (R) underlying cerebral pressure autoregulation are calculated from cerebral perfusion pressure (CPP) divided by cerebral blood flow (F): R = (Pa ICP)/F [5]. Accordingly, to describe cerebral vasoreactivity it is necessary to assess not only arterial blood pressure (Pa) and intracranial pressure (ICP) but also F. The authors behind the PRx method claim that cerebrovascular pressure reactivity may be estimated by observing the response of ICP to changes in Pa. PRx is in this study determined by calculating the correlation coefficient between 30 consecutive data points resulting from the time averaging of ICP and Pa signals with a width of the moving-average window of 8 s [1]. However, in our opinion it is obvious from the equation above that cerebrovascular resistance cannot be calculated unless cerebral blood flow is also assessed. The method of PRx is based on the assumption that the observed change in Pa is the primary and independent cause of the variations in the other three monitored variables. In the validity study of the PRx method Pa was increased by i.v. vasopressor infusion and F was measured utilizing PET-technique [3]. In this defined, experimental situation it is possible that the increase in Pa is the primary and independent cause of the variations in the other variables. Under clinical conditions this is, however, often not the case. During neurocritical care fluctuations in pain, sedation, stress level, local neuronal excitation, etc., will cause changes in cerebral energy metabolism resulting in variations in precapillary vasoconstriction and cerebral blood flow that are not a function of simultaneously occurring changes in Pa. All these sources of error are neglected when PRx is interpreted as a measure of cerebral pressure autoregulation. As the Cambridge group has also suggested that PRx is correlated to cerebral energy metabolism [6] it seems unlikely that this index might be used for continuous estimation pressure autoregulation as well. In their analyses of prognostic threshold levels the authors use mean values for the entire monitoring period for each parameter: ICP, CPP, and PRx. In the study, the monitoring periods vary between 6 h and 20 days. The authors comment on this fact in the section of limitations. However, in our opinion the consequences are more serious than mentioned by the authors and may invalidate the threshold levels arrived at. In patients with brain trauma mortality is usually caused by an increase in ICP and patients who die within the first few days of admission usually have a high ICP. However, patients who initially may have equally high ICP (in this C.-H. Nordstrom (&) T. H. Nielsen Department of Neurosurgery, Odense University Hospital, Odense, Denmark e-mail: carl-henrik.nordstrom@med.lu.se

Introduction: The optimal cerebral perfusion pressure (CPP) following hypoxic-ischemic brain injury (HIBI) is currently unknown. We retrospectively analyzed intracranial monitoring data from a cohort of patients with HIBI to identify a threshold level for CPP that optimizes cerebrovascular pressure reactivity (a surrogate for CA) while limiting the risk of intracranial hypertension and brain tissue hypoxia. Hypothesis: We hypothesized that higher CPP values would be associated with improved cerebrovascular pressure reactivity. Methods: ICP, brain tissue oxygen (P bt O 2 ), MAP, and CPP (defined as MAP - ICP) were recorded continuously and time synchronized for all patients using a bedside monitor (CNS Monitor, Moberg Research). Pressure Reactivity Index (PRx) was calculated as the time varying correlation between MAP and ICP over 5 min intervals updated every minute. The degree of CA impairment (defined as % time PRx &gt; 0.2) was plotted against MAP and CPP, respectively. The relationships between ICP and P bt O 2 versus CPP, as well as ICP and P bt O 2 versus % time PRx &gt; 0.2, were similarly calculated. Results: We analyzed 37 patients (33 cardiac arrest, 4 prolonged hypoxia) with HIBI who underwent intracranial neuromonitoring over a 3 year period. Lower CPP values were associated with higher degrees of CA impairment. The cumulative burden of elevated PRx was significantly lower for CPP values above a cutoff of 85 mmHg compared to lower CPP values (p &lt; 0.001, Wilcoxon rank sum test). A similar cutoff for MAP could not be identified, although lower MAP values were also associated with greater CA impairment. Intracranial hypertension (ICP &gt; 20 mmHg) and brain hypoxia (P bt O2 &lt; 20 mmHg) were both associated with CA impairment (p &lt; 0.001 and p &lt; 0.001, respectively, Wilcoxon rank sum test). Conclusions: Higher CPP and MAP values appear to be associated with improved CA after HIBI. Given that CA impairment is associated with both intracranial hypertension and brain hypoxia, our work reaffirms the notion that higher blood pressure targets may improve outcome after HIBI. The identification of a distinct CPP cutoff for CA optimization suggests that targeting CPP instead of MAP may be advantageous, although further work is required to clarify this issue.

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.

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

To investigate cerebral autoregulatory status in patients with severe traumatic brain injury (TBI), guidelines now suggest active manipulation of mean arterial pressure (MAP). There is a paucity of data, however, describing the effect on intracranial pressure (ICP) when MAP is raised. Consecutive patients with TBI requiring ICP monitoring were enrolled from November 2019 to April 2020. The MAP and ICP were recorded continuously, and clinical annotations were made whenever intravenous vasopressors were commenced or adjusted to defend cerebral perfusion pressure (CPP) targets. A significant change in MAP burden was defined as MAP >100min.mm Hg over 15 min. The primary outcome was the change in ICP burden over the same 15-min period. Bedside and clinical parameters were then compared between these groups. Twenty-eight patients were enrolled, providing 212 clinical events, of which 60 were deemed significant. Over the first 15 min, 65% were associated with a net negative ICP burden. A greater reduction in ICP burden was observed with events occurring in patients without a history of hypotension at scene (p = 0.016), after three days post-injury (p = 0.0018), and where the pressure-reactivity index (PRx) was <0.25 (p = 0.0005) or the ICP amplitude to CPP correlation coefficient (RAC) was <-0.10 (p = 0.0036) at the initiation of vasopressor changes. The ICP burden in the first 15 min was highly correlated with the next 15-min period. In patients with severe TBI requiring ICP monitoring, increasing MAP to pursue a CPP target was followed by a net negative ICP burden in approximately two-thirds of events. These data suggest a MAP challenge may be a useful adjunct in managing intracranial hypertension.

BackgroundA previous retrospective single-centre study suggested that the percentage of time spent with cerebral perfusion pressure (CPP) below the individual lower limit of reactivity (LLR) is associated with mortality in traumatic brain injury (TBI) patients. We aim to validate this in a large multicentre cohort.MethodsRecordings from 171 TBI patients from the high-resolution cohort of the CENTER-TBI study were processed with ICM+ software. We derived LLR as a time trend of CPP at a level for which the pressure reactivity index (PRx) indicates impaired cerebrovascular reactivity with low CPP. The relationship with mortality was assessed with Mann-U test (first 7-day period), Kruskal–Wallis (daily analysis for 7 days), univariate and multivariate logistic regression models. AUCs (CI 95%) were calculated and compared using DeLong’s test.ResultsAverage LLR over the first 7 days was above 60 mmHg in 48% of patients. %time with CPP < LLR could predict mortality (AUC 0.73, p = < 0.001). This association becomes significant starting from the third day post injury. The relationship was maintained when correcting for IMPACT covariates or for high ICP.ConclusionsUsing a multicentre cohort, we confirmed that CPP below LLR was associated with mortality during the first seven days post injury.

The autonomic nervous system exerts tonic control on cerebral vessels, which in turn determine the autoregulation of cerebral blood flow. We hypothesize that the impairment of cerebral autoregulation following traumatic brain injury might be related to the acute failure of the autonomic system. This prospective, observational study included patients with severe traumatic brain injury requiring mechanical ventilation and invasive monitoring of intracranial pressure (ICP) and arterial blood pressure (ABP). Pressure reactivity index (PRx), a validated index of cerebrovascular reactivity, was continuously monitored using bedside computers. Autonomic drive was assessed by means of heart rate variability (HRV) using frequency domain analysis. Eighteen TBI patients were included in the study. Cerebrovascular reactivity impairment (PRx above 0.2) and autonomic failure (low spectral power of HRV) are significantly and independently associated with fatal outcome (P = 0.032 and P < 0.001, respectively). We observed a significant correlation between PRx and HRV spectral power (P < 0.001). The high frequency component of HRV (HF, 0.15-0.4Hz) can be used to predict impaired autoregulation (PRx > 0.2), although sensitivity and specificity are low (ROC AUC = 0.67; P = 0.001). Following traumatic brain injury, autonomic failure and cerebrovascular autoregulation impairment are both associated with fatal outcome. Impairment of cerebrovascular autoregulation and autonomic drive are interdependent phenomena. With some refinements, HRV might become a tool for screening patients at risk for cerebral autoregulation derangement following TBI.

BACKGROUND:We have sought to develop methodology for deriving optimal bispectral index (BIS) values (BISopt) for patients with moderate/severe traumatic brain injury, using continuous monitoring of cerebrovascular reactivity and bispectral electroencephalography.METHODS:Arterial blood pressure, intracranial pressure, and BIS (a bilateral measure that is associated with sedation state) were continuously recorded. The pressure reactivity index, optimal cerebral perfusion pressure (CPPopt), and BISopt were calculated. Using BIS values and the pressure reactivity index, a curve fitting method was applied to determine the minimum value for the pressure reactivity index thus giving the BISopt.RESULTS AND CONCLUSIONS:Identification of BISopt was possible in all of the patients, with both visual inspection of data and using our method of BISopt determination, demonstrating a similarity of median values of 44.62 (35.03–59.98) versus 48 (39.75–57.50) (p = 0.1949). Furthermore, our method outperformed common CPPopt curve fitting methods applied to BISopt with improved percent (%) yields on both the left side 52.1% (36.3–72.4%) versus 31.2% (23.0–48.9%) (p < 0.0001) and the right side 54.1% (35.95–75.9%) versus 33.5% (12.5–47.9%) (p < 0.0001). The BIS values and BISopt were compared with cerebral perfusion pressure, mean arterial pressure, and CPPopt. The results indicated that BISopt’s impact on pressure reactivity was distinct from CPPopt, cerebral perfusion pressure, or mean arterial pressure. Real-time BISopt can be derived from continuous physiologic monitoring of patients with moderate/severe traumatic brain injury. This BISopt value appears to be unassociated with arterial blood pressure or CPPopt, supporting its role as a novel physiologic metric for evaluating cerebral autoregulation. BISopt management to optimize cerebrovascular pressure reactivity should be the subject of future studies in moderate/severe traumatic brain injury.

Pressure reactivity index (PRx) has been proposed as a metric associated with cerebrovascular autoregulatory (CA) function and has been thoroughly investigated in clinical research. In this study, PRx is validated in a porcine cranial window model, developed to visualize pial arteriolar autoregulation and its limits. We measured arterial blood pressure, intracranial pressure, pial arteriolar diameter, and red blood cell (RBC) velocity in a closed cranial window piglet model during gradual balloon catheter-induced arterial hypotension (n = 10) or hypertension (n = 10). CA limits were derived through piecewise linear regression of calculated RBC flux vs cerebral perfusion pressure (CPP), leading for each arteriole to 1 lower limit of autoregulation (LLA) and 2 upper limits of autoregulation (ULA1 and ULA2). Autoregulation limits were compared with PRx thresholds, and receiver operating curve analysis was performed with and without CPP binning. A linear mixed effects model of PRx was performed. Receiver operating curve analysis indicated an area under the curve (AUC) for LLA prediction by a PRx of 0.65 (95% CI: 0.64-0.67) and 0.77 (95% CI: 0.69-0.86) without and with CPP binning, respectively. The AUC for ULA1 prediction by PRx was 0.69 (95% CI: 0.68-0.69) without and 0.75 (95% CI: 0.68-0.82) with binning. The AUC for ULA2 prediction was 0.55 (95% CI: 0.55-0.58) without and 0.63 (95% CI 0.53-0.72) with binning. The sensitivity and specificity of binned PRx were 65%/90% for LLA, 69%/71% for ULA1, and 59%/74% for ULA2, showing wide interindividual variability. In the linear mixed effects model, pial arteriolar diameter changes were significantly associated with PRx changes ( P = .002), whereas RBC velocity ( P = .28) and RBC flux ( P = .24) were not. We conclude that PRx is predominantly determined by pial arteriolar diameter changes and moderately predicts CA limits. Performance to detect the CA limits varied highly on an individual level. Active therapeutic strategies based on PRx and the associated correlation metrics should incorporate these limitations.

Objective: To investigate the temporal relationship between cerebrovascular pressure reactivity and brain tissue oxygenation in patients with severe head injury. Methods: In 40 patients, brain tissue oxygenation and intracranial pressure...

ObjectiveWe aimed to compare the prevalence and multimodal associations of mitochondrial dysfunction as defined by published cerebral-microdialysis-based criteria versus our novel multimodality-monitoring-based criteria in acute traumatic brain injury patients.MethodsWe retrospectively analyzed neurocritical care monitoring data from 619 acute traumatic brain injury patients. Monitoring modalities included cerebral microdialysis, intracranial pressure, brain tissue oxygenation, cerebral perfusion pressure, and the pressure reactivity index. The cerebral-microdialysis-based criteria we compared combine an elevated lactate/pyruvate ratio (25 or 30) with raised concentrations of lactate (2.5 mM) or pyruvate (70 μM or 120 μM). Our multimodality-monitoring-based criteria comprise a consistent lactate/pyruvate ratio > 25 with intracranial pressure ≤ 20 mmHg, brain tissue oxygenation ≥ 15 mmHg, a pressure reactivity index ≤ 0.3, and cerebral glucose ≥ 1.0 mM.ResultsAcross 592 analyzable patients, a lactate/pyruvate ratio > 25 was common, with a median prevalence of 48.9% (41.5% with consistency) and a U-shaped, bimodal distribution. A lactate/pyruvate ratio > 25 was associated with lower glucose and higher glycerol, and when accompanied by high pyruvate (> 120 μM), this derangement was further distinguished by higher glutamate and cerebral perfusion pressure. Using multimodal criteria on a cohort of 268 patients, consistent mitochondrial dysfunction was identified in 25.7% to 41.0% of patients, often in the absence of other physiological derangements.ConclusionsMany acute traumatic brain injury patients constantly demonstrate neurometabolic derangements, among which clinical mitochondrial dysfunction is highly prevalent despite normal cerebral pressure, oxygenation, and perfusion. There is necessity for targeted, neurometabolic therapies in neurocritical care that address this abnormality.

The role of extra-cranial injury burden and systemic injury response on cerebrovascular response in traumatic brain injury (TBI) is poorly documented. This study preliminarily assesses the association between admission features of extra-cranial injury burden on cerebrovascular reactivity. Using the Collaborative European Neurotrauma Effectiveness Research in TBI High-Resolution ICU (HR ICU) sub-study cohort, we evaluated those patients with both archived high-frequency digital intra-parenchymal intra-cranial pressure monitoring data of a minimum of 6 h in duration, and the presence of a digital copy of their admission computed tomography (CT) scan. Digital physiologic signals were processed for pressure reactivity index (PRx) and both the percent time above defined PRx thresholds and mean hourly dose above threshold. This was conducted for both the first 72 h and entire duration of recording. Admission extra-cranial injury characteristics and CT injury scores were obtained from the database, with quantitative contusion, edema, intraventricular hemorrhage, and extra-axial lesion volumes were obtained via semi-automated segmentation. Comparison between admission extra-cranial markers of injury and PRx metrics was conducted using Mann-Whitney U testing, and logistic regression techniques, adjusting for known CT injury metrics associated with impaired PRx. A total of 165 patients were included. Evaluating the entire ICU recording period, there was limited association between metrics of extra-cranial injury burden and impaired cerebrovascular reactivity. Using the first 72 h of recording, admission temperature (p = 0.042) and white blood cell % (WBC %; p = 0.013) were statistically associated with impaired cerebrovascular reactivity on Mann-Whitney U and univariate logistic regression. After adjustment for admission age, pupillary status, GCS motor score, pre-hospital hypoxia/hypotension, and intra-cranial CT characteristics associated with impaired reactivity, temperature (p = 0.021) and WBC % (p = 0.013) remained significantly associated with mean PRx values above +0.25 and +0.35, respectively. Markers of extra-cranial injury burden and systemic injury response do not appear to be strongly associated with impaired cerebrovascular reactivity in TBI during both the initial and entire ICU stay.