Pathophysiological characterization of traumatic brain injury using novel analytical methods

Severity of traumatic brain injury is usually classified by Glasgow coma scale (GCS) as “mild”, "moderate" or "severe’, which does not capture the heterogeneity of the disease. According to current guidelines, intracranial pressure (ICP) should not exceed 22 mmHg, with no further recommendations concerning individualization or tolerable duration of intracranial hypertension. The aims of this thesis were to identify subgroups of patients beyond characterization using GCS, and to investigate the impact of duration and magnitude of intracranial hypertension on outcome, using data from the observational prospective study Collaborative European neurotrauma effectiveness research in TBI (CENTER-TBI). To investigate the temporal aspect of tolerable ICP elevations, we examined the correlation between dose of ICP and outcome represented by 6-month Glasgow outcome scale extended (GOSE). ICP dose was represented both by the number of events above thresholds for ICP magnitude and duration and by area under the ICP curve (i.e., “pressure time dose” (PTD)). A variation in tolerable ICP thresholds of 18 mmHg +/- 4 mmHg (2 standard deviations (SD)) for events with duration longer than five minutes was identified using a bootstrapping technique. PTD was correlated to both mortality and unfavorable outcome. A cerebrovascular autoregulation (CA) dependent ICP tolerability was identified. If CA was impaired, no tolerable ICP magnitude and duration thresholds were identified, while if CA was intact, both 19 mmHg for 5 minutes or longer and 15 mmHg for 50 minutes or longer were correlated to worse outcome. While no significant difference in PTD was seen between favorable and unfavorable outcome if CA was intact, there was a significant difference if CA was impaired. In a multivariable analysis, PTD did not remain a significant predictor of outcome when adjusting for other known predictors in TBI. In a causal inference analysis, both cerebrovascular autoregulation status and ICP-lowering therapies represented by the therapy intensity level (TIL) have a directional relationship with outcome. However, no direct causal relationship of ICP towards outcome was found. By applying an unsupervised clustering method, we identified six distinct admission clusters defined by GCS, lactate, oxygen saturation (SpO2), creatinine, glucose, base excess, pH, PaCO2, and body temperature. These clusters can be summarized in clinical presentation and metabolic profile. When clustering longitudinal features during the first week in the intensive care unit (ICU), no optimal number of clusters could be seen. However, glucose variation, a panel of brain biomarkers, and creatinine consistently described trajectories. Although no information on outcome was included in the models, both admission clusters and trajectories showed clear outcome differences, with mortality from 7 to 40% in the admission clusters and 4 to 85% in the trajectories. Adding cluster or trajectory labels to the established outcome prediction IMPACT model significantly improved outcome predictions. The results in this thesis support the importance of cerebrovascular autoregulation status as it was found that CA status was more informative towards outcome than ICP magnitude and duration. There was a variation in tolerable ICP intensity and duration dependent on whether CA was intact. Distinct clusters defined by GCS and metabolic profiles related to outcome suggest the importance of an extracranial evaluation in addition to GCS in TBI patients. Longitudinal trajectories of TBI patients in the ICU are highly characterized by glucose variation, brain biomarkers and creatinine

Spoken and written narratives in Swedish children and adolescents with hearing impairment

Twenty 10- to 18-year-old children and adolescents with varying degrees of hearing impairment (HI) and hearing aids (HA), ranging from mild-moderate to severe, produced picture-elicited narratives in a spoken and written version. Their performance was compared to that of 63 normally hearing (NH) peers within the same age span. The participants with HI and NH showed similar patterns regarding intragroup correlations between corresponding measures of spoken and written narratives. However, the participants with HI had significantly less diverse language than the NH group. The participants with poorer hearing (higher best ear hearing level [BEHL]) produced spoken and written narratives comprising more content words and they also produced written narratives that were less lexically diverse than the participants with better hearing (lower BEHL). The difference as to lexical skills emphasizes the importance of focusing on these skills in the group of children with HI. However, the results give support for a quite optimistic view on the development of narration in children with HI with HA, at least for picture-elicited narratives

Contribution of clinical course to outcome after traumatic brain injury: mining patient trajectories from European intensive care unit data

Existing methods to characterise the evolving condition of traumatic brain injury (TBI) patients in the intensive care unit (ICU) do not capture the context necessary for individualising treatment. We aimed to develop a modelling strategy which integrates all data stored in medical records to produce an interpretable disease course for each TBI patient's ICU stay. From a prospective, European cohort (n=1,550, 65 centres, 19 countries) of TBI patients, we extracted all 1,166 variables collected before or during ICU stay as well as 6-month functional outcome on the Glasgow Outcome Scale-Extended (GOSE). We trained recurrent neural network models to map a token-embedded time series representation of all variables (including missing data) to an ordinal GOSE prognosis every 2 hours. With repeated cross-validation, we evaluated calibration and the explanation of ordinal variance in GOSE with Somers' Dxy. Furthermore, we applied TimeSHAP to calculate the contribution of variables and prior timepoints towards transitions in patient trajectories. Our modelling strategy achieved calibration at 8 hours, and the full range of variables explained up to 52% (95% CI: 50-54%) of the variance in ordinal functional outcome. Up to 91% (90-91%) of this explanation was derived from pre-ICU and admission information. Information collected in the ICU increased explanation (by up to 5% [4-6%]), though not enough to counter poorer performance in longer-stay (>5.75 days) patients. Static variables with the highest contributions were physician prognoses and certain demographic and CT features. Among dynamic variables, markers of intracranial hypertension and neurological function contributed the most. Whilst static information currently accounts for the majority of functional outcome explanation, our data-driven analysis highlights investigative avenues to improve dynamic characterisation of longer-stay patients

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study.

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 ± 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels

Differences between Men and Women in Treatment and Outcome after Traumatic Brain Injury

Traumatic brain injury (TBI) is a significant cause of disability, but little is known about sex and gender differences after TBI. We aimed to analyze the association between sex/gender, and the broad range of care pathways, treatment characteristics, and outcomes following mild and moderate/severe TBI. We performed mixed-effects regression analyses in the prospective multi-center Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, stratified for injury severity and age, and adjusted for baseline characteristics. Outcomes were various care pathway and treatment variables, and 6-month measures of functional outcome, health-related quality of life (HRQoL), post-concussion symptoms (PCS), and mental health symptoms. The study included 2862 adults (36% women) with mild (mTBI; Glasgow Coma Scale [GCS] score 13–15), and 1333 adults (26% women) with moderate/severe TBI (GCS score 3–12). Women were less likely to be admitted to the intensive care unit (ICU; odds ratios [OR] 0.6, 95% confidence interval [CI]: 0.4-0.8) following mTBI. Following moderate/severe TBI, women had a shorter median hospital stay (OR 0.7, 95% CI: 0.5-1.0). Following mTBI, women had poorer outcomes; lower Glasgow Outcome Scale Extended (GOSE; OR 1.4, 95% CI: 1.2-1.6), lower generic and disease-specific HRQoL, and more severe PCS, depression, and anxiety. Among them, women under age 45 and above age 65 years showed worse 6-month outcomes compared with men of the same age. Following moderate/severe TBI, there was no difference in GOSE (OR 0.9, 95% CI: 0.7-1.2), but women reported more severe PCS (OR 1.7, 95% CI: 1.1-2.6). Men and women differ in care pathways and outcomes following TBI. Women generally report worse 6-month outcomes, but the size of differences depend on TBI severity and age. Future studies should examine factors that explain these differences

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 ± 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 ± 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels

Extended Coagulation Profiling in Isolated Traumatic Brain Injury:A CENTER-TBI Analysis

Background: Trauma-induced coagulopathy in traumatic brain injury (TBI) remains associated with high rates of complications, unfavorable outcomes, and mortality. The underlying mechanisms are largely unknown. Embedded in the prospective multinational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, coagulation profiles beyond standard conventional coagulation assays were assessed in patients with isolated TBI within the very early hours of injury. Methods: Results from blood samples (citrate/EDTA) obtained on hospital admission were matched with clinical and routine laboratory data of patients with TBI captured in the CENTER-TBI central database. To minimize confounding factors, patients with strictly isolated TBI (iTBI) (n = 88) were selected and stratified for coagulopathy by routine international normalized ratio (INR): (1) INR &lt; 1.2 and (2) INR ≥ 1.2. An INR &gt; 1.2 has been well adopted over time as a threshold to define trauma-related coagulopathy in general trauma populations. The following parameters were evaluated: quick’s value, activated partial thromboplastin time, fibrinogen, thrombin time, antithrombin, coagulation factor activity of factors V, VIII, IX, and XIII, protein C and S, plasminogen, D-dimer, fibrinolysis-regulating parameters (thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor 1, antiplasmin), thrombin generation, and fibrin monomers. Results: Patients with iTBI with INR ≥ 1.2 (n = 16) had a high incidence of progressive intracranial hemorrhage associated with increased mortality and unfavorable outcome compared with patients with INR &lt; 1.2 (n = 72). Activity of coagulation factors V, VIII, IX, and XIII dropped on average by 15–20% between the groups whereas protein C and S levels dropped by 20%. With an elevated INR, thrombin generation decreased, as reflected by lower peak height and endogenous thrombin potential (ETP), whereas the amount of fibrin monomers increased. Plasminogen activity significantly decreased from 89% in patients with INR &lt; 1.2 to 76% in patients with INR ≥ 1.2. Moreover, D-dimer levels significantly increased from a mean of 943 mg/L in patients with INR &lt; 1.2 to 1,301 mg/L in patients with INR ≥ 1.2. Conclusions: This more in-depth analysis beyond routine conventional coagulation assays suggests a counterbalanced regulation of coagulation and fibrinolysis in patients with iTBI with hemostatic abnormalities. We observed distinct patterns involving key pathways of the highly complex and dynamic coagulation system that offer windows of opportunity for further research. Whether the changes observed on factor levels may be relevant and explain the worse outcome or the more severe brain injuries by themselves remains speculative.</p

Rehabilitation and outcomes after complicated vs uncomplicated mild TBI:results from the CENTER-TBI study

Background: Despite existing guidelines for managing mild traumatic brain injury (mTBI), evidence-based treatments are still scarce and large-scale studies on the provision and impact of specific rehabilitation services are needed. This study aimed to describe the provision of rehabilitation to patients after complicated and uncomplicated mTBI and investigate factors associated with functional outcome, symptom burden, and TBI-specific health-related quality of life (HRQOL) up to six months after injury. Methods: Patients (n = 1379) with mTBI from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study who reported whether they received rehabilitation services during the first six months post-injury and who participated in outcome assessments were included. Functional outcome was measured with the Glasgow Outcome Scale – Extended (GOSE), symptom burden with the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and HRQOL with the Quality of Life after Brain Injury – Overall Scale (QOLIBRI-OS). We examined whether transition of care (TOC) pathways, receiving rehabilitation services, sociodemographic (incl. geographic), premorbid, and injury-related factors were associated with outcomes using regression models. For easy comparison, we estimated ordinal regression models for all outcomes where the scores were classified based on quantiles. Results: Overall, 43% of patients with complicated and 20% with uncomplicated mTBI reported receiving rehabilitation services, primarily in physical and cognitive domains. Patients with complicated mTBI had lower functional level, higher symptom burden, and lower HRQOL compared to uncomplicated mTBI. Rehabilitation services at three or six months and a higher number of TOC were associated with unfavorable outcomes in all models, in addition to pre-morbid psychiatric problems. Being male and having more than 13 years of education was associated with more favorable outcomes. Sustaining major trauma was associated with unfavorable GOSE outcome, whereas living in Southern and Eastern European regions was associated with lower HRQOL. Conclusions: Patients with complicated mTBI reported more unfavorable outcomes and received rehabilitation services more frequently. Receiving rehabilitation services and higher number of care transitions were indicators of injury severity and associated with unfavorable outcomes. The findings should be interpreted carefully and validated in future studies as we applied a novel analytic approach. Trial registration: ClinicalTrials.gov NCT02210221.</p