Spreading depolarization and angiographic spasm are separate mediators of delayed infarcts

In DISCHARGE-1, a recent Phase III diagnostic trial in aneurysmal subarachnoid haemorrhage patients, spreading depolarization variables were found to be an independent real-time biomarker of delayed cerebral ischaemia. We here investigated based on prospectively collected data from DISCHARGE-1 whether delayed infarcts in the anterior, middle, or posterior cerebral artery territories correlate with (i) extravascular blood volumes; (ii) predefined spreading depolarization variables, or proximal vasospasm assessed by either (iii) digital subtraction angiography or (iv) transcranial Doppler-sonography; and whether spreading depolarizations and/or vasospasm are mediators between extravascular blood and delayed infarcts. Relationships between variable groups were analysed using Spearman correlations in 136 patients. Thereafter, principal component analyses were performed for each variable group. Obtained components were included in path models with a priori defined structure. In the first path model, we only included spreading depolarization variables, as our primary interest was to investigate spreading depolarizations. Standardised path coefficients were 0.22 for the path from extravascular bloodcomponent to depolarizationcomponent (P = 0.010); and 0.44 for the path from depolarizationcomponent to the first principal component of delayed infarct volume (P < 0.001); but only 0.07 for the direct path from bloodcomponent to delayed infarctcomponent (P = 0.36). Thus, the role of spreading depolarizations as a mediator between blood and delayed infarcts was confirmed. In the principal component analysis of extravascular blood volume, intraventricular haemorrhage was not represented in the first component. Therefore, based on the correlation analyses, we also constructed another path model with bloodcomponent without intraventricular haemorrhage as first and intraventricular haemorrhage as second extrinsic variable. We found two paths, one from (subarachnoid) bloodcomponent to delayed infarctcomponent with depolarizationcomponent as mediator (path coefficients from bloodcomponent to depolarizationcomponent = 0.23, P = 0.03; path coefficients from depolarizationcomponent to delayed infarctcomponent = 0.29, P = 0.002), and one from intraventricular haemorrhage to delayed infarctcomponent with angiographic vasospasmcomponent as mediator variable (path coefficients from intraventricular haemorrhage to vasospasmcomponent = 0.24, P = 0.03; path coefficients from vasospasmcomponent to delayed infarctcomponent = 0.35, P < 0.001). Human autopsy studies shaped the hypothesis that blood clots on the cortex surface suffice to cause delayed infarcts beneath the clots. Experimentally, clot-released factors induce cortical spreading depolarizations that trigger (i) neuronal cytotoxic oedema and (ii) spreading ischaemia. The statistical mediator role of spreading depolarization variables between subarachnoid blood volume and delayed infarct volume supports this pathogenetic concept. We did not find that angiographic vasospasm triggers spreading depolarizations, but angiographic vasospasm contributed to delayed infarct volume. This could possibly result from enhancement of spreading depolarization-induced spreading ischaemia by reduced upstream blood supply.Peer Reviewe

Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions

How does infarction in victims of stroke and other types of acute brain injury expand to its definitive size in subsequent days? Spontaneous depolarizations that repeatedly spread across the cerebral cortex, sometimes at remarkably regular intervals, occur in patients with all types of injury. Here, we show experimentally with in vivo real-time imaging that similar, spontaneous depolarizations cycle repeatedly around ischaemic lesions in the cerebral cortex, and enlarge the lesion in step with each cycle. This behaviour results in regular periodicity of depolarization when monitored at a single point in the lesion periphery. We present evidence from clinical monitoring to suggest that depolarizations may cycle in the ischaemic human brain, perhaps explaining progressive growth of infarction. Despite their apparent detrimental role in infarct growth, we argue that cycling of depolarizations around lesions might also initiate upregulation of the neurobiological responses involved in repair and remodelling

Machine learning algorithms performed no better than regression models for prognostication in traumatic brain injury

Objective: We aimed to explore the added value of common machine learning (ML) algorithms for prediction of outcome for moderate and severe traumatic brain injury. Study Design and Setting: We performed logistic regression (LR), lasso regression, and ridge regression with key baseline predictors in the IMPACT-II database (15 studies, n = 11,022). ML algorithms included support vector machines, random forests, gradient boosting machines, and artificial neural networks and were trained using the same predictors. To assess generalizability of predictions, we performed internal, internal-external, and external validation on the recent CENTER-TBI study (patients with Glasgow Coma Scale <13, n = 1,554). Both calibration (calibration slope/intercept) and discrimination (area under the curve) was quantified. Results: In the IMPACT-II database, 3,332/11,022 (30%) died and 5,233(48%) had unfavorable outcome (Glasgow Outcome Scale less than 4). In the CENTER-TBI study, 348/1,554(29%) died and 651(54%) had unfavorable outcome. Discrimination and calibration varied widely between the studies and less so between the studied algorithms. The mean area under the curve was 0.82 for mortality and 0.77 for unfavorable outcomes in the CENTER-TBI study. Conclusion: ML algorithms may not outperform traditional regression approaches in a low-dimensional setting for outcome prediction after moderate or severe traumatic brain injury. Similar to regression-based prediction models, ML algorithms should be rigorously validated to ensure applicability to new populations

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Quality indicators for patients with traumatic brain injury in European intensive care units: a CENTER-TBI study

Abstract: Background: The aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measurement and improvement. Methods: Our analysis was based on 2006 adult patients admitted to 54 ICUs between 2014 and 2018, enrolled in the CENTER-TBI study. Indicator scores were calculated as percentage adherence for structure and process indicators and as event rates or median scores for outcome indicators. Feasibility was quantified by the completeness of the variables. Discriminability was determined by the between-centre variation, estimated with a random effect regression model adjusted for case-mix severity and quantified by the median odds ratio (MOR). Statistical uncertainty of outcome indicators was determined by the median number of events per centre, using a cut-off of 10. Results: A total of 26/42 indicators could be calculated from the CENTER-TBI database. Most quality indicators proved feasible to obtain with more than 70% completeness. Sub-optimal adherence was found for most quality indicators, ranging from 26 to 93% and 20 to 99% for structure and process indicators. Significant (p < 0.001) between-centre variation was found in seven process and five outcome indicators with MORs ranging from 1.51 to 4.14. Statistical uncertainty of outcome indicators was generally high; five out of seven had less than 10 events per centre. Conclusions: Overall, nine structures, five processes, but none of the outcome indicators showed potential for quality improvement purposes for TBI patients in the ICU. Future research should focus on implementation efforts and continuous reevaluation of quality indicators. Trial registration: The core study was registered with ClinicalTrials.gov, number NCT02210221, registered on August 06, 2014, with Resource Identification Portal (RRID: SCR_015582)

Quality indicators for patients with traumatic brain injury in European intensive care units: a CENTER-TBI study

Abstract: Background: The aim of this study is to validate a previously published consensus-based quality indicator set for the management of patients with traumatic brain injury (TBI) at intensive care units (ICUs) in Europe and to study its potential for quality measurement and improvement. Methods: Our analysis was based on 2006 adult patients admitted to 54 ICUs between 2014 and 2018, enrolled in the CENTER-TBI study. Indicator scores were calculated as percentage adherence for structure and process indicators and as event rates or median scores for outcome indicators. Feasibility was quantified by the completeness of the variables. Discriminability was determined by the between-centre variation, estimated with a random effect regression model adjusted for case-mix severity and quantified by the median odds ratio (MOR). Statistical uncertainty of outcome indicators was determined by the median number of events per centre, using a cut-off of 10. Results: A total of 26/42 indicators could be calculated from the CENTER-TBI database. Most quality indicators proved feasible to obtain with more than 70% completeness. Sub-optimal adherence was found for most quality indicators, ranging from 26 to 93% and 20 to 99% for structure and process indicators. Significant (p < 0.001) between-centre variation was found in seven process and five outcome indicators with MORs ranging from 1.51 to 4.14. Statistical uncertainty of outcome indicators was generally high; five out of seven had less than 10 events per centre. Conclusions: Overall, nine structures, five processes, but none of the outcome indicators showed potential for quality improvement purposes for TBI patients in the ICU. Future research should focus on implementation efforts and continuous reevaluation of quality indicators. Trial registration: The core study was registered with ClinicalTrials.gov, number NCT02210221, registered on August 06, 2014, with Resource Identification Portal (RRID: SCR_015582)

Changing care pathways and between-center practice variations in intensive care for traumatic brain injury across Europe: a CENTER-TBI analysis

Abstract: Purpose: To describe ICU stay, selected management aspects, and outcome of Intensive Care Unit (ICU) patients with traumatic brain injury (TBI) in Europe, and to quantify variation across centers. Methods: This is a prospective observational multicenter study conducted across 18 countries in Europe and Israel. Admission characteristics, clinical data, and outcome were described at patient- and center levels. Between-center variation in the total ICU population was quantified with the median odds ratio (MOR), with correction for case-mix and random variation between centers. Results: A total of 2138 patients were admitted to the ICU, with median age of 49 years; 36% of which were mild TBI (Glasgow Coma Scale; GCS 13–15). Within, 72 h 636 (30%) were discharged and 128 (6%) died. Early deaths and long-stay patients (> 72 h) had more severe injuries based on the GCS and neuroimaging characteristics, compared with short-stay patients. Long-stay patients received more monitoring and were treated at higher intensity, and experienced worse 6-month outcome compared to short-stay patients. Between-center variations were prominent in the proportion of short-stay patients (MOR = 2.3, p < 0.001), use of intracranial pressure (ICP) monitoring (MOR = 2.5, p < 0.001) and aggressive treatments (MOR = 2.9, p < 0.001); and smaller in 6-month outcome (MOR = 1.2, p = 0.01). Conclusions: Half of contemporary TBI patients at the ICU have mild to moderate head injury. Substantial between-center variations exist in ICU stay and treatment policies, and less so in outcome. It remains unclear whether admission of short-stay patients represents appropriate prudence or inappropriate use of clinical resources

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Primary versus early secondary referral to a specialized neurotrauma center in patients with moderate/severe traumatic brain injury: a CENTER TBI study

Funder: ZNS - Hannelore Kohl Stiftung; doi: http://dx.doi.org/10.13039/501100007731Funder: Integra LifeSciences CorporationFunder: OneMindAbstract: Background: Prehospital care for patients with traumatic brain injury (TBI) varies with some emergency medical systems recommending direct transport of patients with moderate to severe TBI to hospitals with specialist neurotrauma care (SNCs). The aim of this study is to assess variation in levels of early secondary referral within European SNCs and to compare the outcomes of directly admitted and secondarily transferred patients. Methods: Patients with moderate and severe TBI (Glasgow Coma Scale < 13) from the prospective European CENTER-TBI study were included in this study. All participating hospitals were specialist neuroscience centers. First, adjusted between-country differences were analysed using random effects logistic regression where early secondary referral was the dependent variable, and a random intercept for country was included. Second, the adjusted effect of early secondary referral on survival to hospital discharge and functional outcome [6 months Glasgow Outcome Scale Extended (GOSE)] was estimated using logistic and ordinal mixed effects models, respectively. Results: A total of 1347 moderate/severe TBI patients from 53 SNCs in 18 European countries were included. Of these 1347 patients, 195 (14.5%) were admitted after early secondary referral. Secondarily referred moderate/severe TBI patients presented more often with a CT abnormality: mass lesion (52% vs. 34%), midline shift (54% vs. 36%) and acute subdural hematoma (77% vs. 65%). After adjusting for case-mix, there was a large European variation in early secondary referral, with a median OR of 1.69 between countries. Early secondary referral was not associated with functional outcome (adjusted OR 1.07, 95% CI 0.78–1.69), nor with survival at discharge (1.05, 0.58–1.90). Conclusions: Across Europe, substantial practice variation exists in the proportion of secondarily referred TBI patients at SNCs that is not explained by case mix. Within SNCs early secondary referral does not seem to impact functional outcome and survival after stabilisation in a non-specialised hospital. Future research should identify which patients with TBI truly benefit from direct transportation