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IntroductionManagement of traumatic brain injury (TBI) includes invasive monitoring to prevent secondary brain injuries. Intracranial pressure (ICP) monitor is the main measurement used to that intent but cerebral hypoxia can occur despite normal ICP. This study will assess whether the addition of a brain tissue oxygenation (PbtO2) monitor prevents more secondary injuries that will translate into improved functional outcome.Methods and analysisMulticentre, randomised, blinded-endpoint comparative effectiveness study enrolling 1094 patients with severe TBI monitored with both ICP and PbtO2. Patients will be randomised to medical management guided by ICP alone (treating team blinded to PbtO2 values) or both ICP and PbtO2. Management is protocolised according to international guidelines in a tiered approach fashion to maintain ICP <22 mm Hg and PbtO2 >20 mm Hg. ICP and PbtO2 will be continuously recorded for a minimum of 5 days. The primary outcome measure is the Glasgow Outcome Scale-Extended performed at 180 (±30) days by a blinded central examiner. Favourable outcome is defined according to a sliding dichotomy where the definition of favourable outcome varies according to baseline severity. Severity will be defined according to the probability of poor outcome predicted by the IMPACT core model. A large battery of secondary outcomes including granular neuropsychological and quality of life measures will be performed.Ethics and disseminationThis has been approved by Advarra Ethics Committee (Pro00030585). Results will be presented at scientific meetings and published in peer-reviewed publications.Trial registration numberClinicalTrials.gov Registry (NCT03754114).

Pathological waves of spreading mass neuronal depolarisation arise repeatedly in injured, but potentially salvageable, grey matter in 50–60% of patients after traumatic brain injury (TBI). We aimed to ascertain whether spreading depolarisations are independently associated with unfavourable neurological outcome. We did a prospective, observational, multicentre study at seven neurological centres. We enrolled 109 adults who needed neurosurgery for acute TBI. Spreading depolarisations were monitored by electrocorticography during intensive care and were classified as cortical spreading depression (CSD) if they took place in spontaneously active cortex or as isoelectric spreading depolarisation (ISD) if they took place in isoelectric cortex. Investigators who treated patients and assessed outcome were masked to electrocorticographic results. Scores on the extended Glasgow outcome scale at 6 months were fitted to a multivariate model by ordinal regression. Prognostic score (based on variables at admission, as validated by the IMPACT studies) and spreading depolarisation category (none, CSD only, or at least one ISD) were assessed as outcome predictors. Six individuals were excluded because of poor-quality electrocorticography. A total of 1328 spreading depolarisations arose in 58 (56%) patients. In 38 participants, all spreading depolarisations were classified as CSD; 20 patients had at least one ISD. By multivariate analysis, both prognostic score (p=0·0009) and spreading depolarisation category (p=0·0008) were significant predictors of neurological outcome. CSD and ISD were associated with an increased risk of unfavourable outcome (common odds ratios 1·56 [95% CI 0·72–3·37] and 7·58 [2·64–21·8], respectively). Addition of depolarisation category to the regression model increased the proportion of variance in outcome that could be attributed to predictors from 9% to 22%, compared with the prognostic score alone. Spreading depolarisations were associated with unfavourable outcome, after controlling for conventional prognostic variables. The possibility that spreading depolarisations have adverse effects on the traumatically injured brain, and therefore might be a target in the treatment of TBI, deserves further research. US Army CDMRP PH/TBI research programme.

Background Anti-epileptic drugs are commonly used for seizure prophylaxis after neurological injury. We performed a study comparing intravenous (IV) levetiracetam (LEV) to IV phenytoin (PHT) for seizure prophylaxis after neurological injury. Methods In this prospective, single-center, randomized, single-blinded comparative trial of LEV versus PHT (2:1 ratio) in patients with severe traumatic brain injury (sTBI) or subarachnoid hemorrhage (NCT00618436) patients received IV load with either LEV or fosphenytoin followed by standard IV doses of LEV or PHT. Doses were adjusted to maintain therapeutic serum PHT concentrations or if patients had seizures. Continuous EEG (cEEG) monitoring was performed for the initial 72 h; outcome data were collected. Results A total of 52 patients were randomized (LEV = 34; PHT = 18); 89% with sTBI. When controlling for baseline severity, LEV patients experienced better long-term outcomes than those on PHT; the Disability Rating Scale score was lower at 3 months ( P  = 0.042) and the Glasgow Outcomes Scale score was higher at 6 months ( P  = 0.039). There were no differences between groups in seizure occurrence during cEEG (LEV 5/34 vs. PHT 3/18; P  = 1.0) or at 6 months (LEV 1/20 vs. PHT 0/14; P  = 1.0), mortality (LEV 14/34 vs. PHT 4/18; P  = 0.227). There were no differences in side effects between groups (all P  > 0.15) except for a lower frequency of worsened neurological status ( P  = 0.024), and gastrointestinal problems ( P  = 0.043) in LEV-treated patients. Conclusions This study of LEV versus PHT for seizure prevention in the NSICU showed improved long-term outcomes of LEV-treated patients vis-à-vis PHT-treated patients. LEV appears to be an alternative to PHT for seizure prophylaxis in this setting.

Early prediction of outcomes after traumatic brain injury (TBI) is often difficult. To improve prognostic accuracy soon after trauma, we compared different radiological modalities and anatomical injury distribution in a group of adult TBI patients. The four methods studied were computed tomography (CT), magnetic resonance imaging (MRI) with T2-weighted imaging (T2WI), fluid-attenuated inversion recovery (FLAIR) imaging, and susceptibility weighted imaging (SWI). The objective of this study was to identify which modality and anatomic model best predict outcome. The patient population consisted of 38 adults admitted between February 2001 and May 2003. Early CT, T2WI, FLAIR, and SWI were obtained for each patient as well as a Glasgow Outcome Score (GOS) between 0.1 and 22 months (mean 9.2 months) after injury. Using a semi-automated computer method, intraparenchymal lesions were traced, measured, and converted to lesion volumes based on slice thickness and pixel size. Lesions were assigned to zones and regions. Outcomes were dichotomized into good (GOS 4–5) and poor (GOS 1–3) outcome groups. Brain injury detected by imaging was analyzed by median total lesion volume, median volume per lesion, and median number of lesions per outcome group. T2WI and FLAIR imaging most consistently discriminated between good and poor outcomes by median total lesion volume, median volume per lesion, and median number of lesions. In addition, T2WI and FLAIR imaging most consistently discriminated between good and poor outcomes by zonal distribution. While SWI rarely discriminated by outcome, it was very sensitive to intraparenchymal injury and its optimal use in evaluating TBI is unclear. SWI and other new imaging modalities should be further studied to fully evaluate their prognostic utility in TBI evaluation.

Successful donation of organs after cardiac death (DCD) requires identification of patients who will die within 60 min of withdrawal of life-sustaining treatment (WLST). We aimed to validate a straightforward model to predict the likelihood of death within 60 min of WLST in patients with irreversible brain injury. In this multicentre, observational study, we prospectively enrolled consecutive comatose patients with irreversible brain injury undergoing WLST at six medical centres in the USA and the Netherlands. We assessed four clinical characteristics (corneal reflex, cough reflex, best motor response, and oxygenation index) as predictor variables, which were selected on the basis of previous findings. We excluded patients who had brain death or were not intubated. The primary endpoint was death within 60 min of WLST. We used univariate and multivariable logistic regression analyses to assess associations with predictor variables. Points attributed to each variable were summed to create a predictive score for cardiac death in patients in neurocritical state (the DCD-N score). We assessed performance of the score using area under the curve analysis. We included 178 patients, 82 (46%) of whom died within 60 min of WLST. Absent corneal reflexes (odds ratio [OR] 2·67, 95% CI 1·19–6·01; p=0·0173; 1 point), absent cough reflex (4·16, 1·79–9·70; p=0·0009; 2 points), extensor or absent motor responses (2·99, 1·22–7·34; p=0·0168; 1 point), and an oxygenation index score of more than 3·0 (2·31, 1·10–4·88; p=0·0276; 1 point) were predictive of death within 60 min of WLST. 59 of 82 patients who died within 60 min of WLST had DCD-N scores of 3 or more (72% sensitivity), and 75 of 96 of those who did not die within this interval had scores of 0–2 (78% specificity); taking into account the prevalence of death within 60 min in this population, a score of 3 or more was translated into a 74% chance of death within 60 min (positive predictive value) and a score of 0–2 translated into a 77% chance of survival beyond 60 min (negative predictive value). The DCD-N score can be used to predict potential candidates for DCD in patients with non-survivable brain injury. However, this score needs to be tested specifically in a cohort of potential donors participating in DCD protocols. None.

Hutchinson et al. 1 report in the Journal the results of the Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) trial, which compared decompressive craniectomy with continued medical management for refractory elevation of intracranial pressure after severe traumatic brain injury. Urgent treatment of patients with such an injury focuses on minimizing secondary brain injury, particularly from increased intracranial pressure. When common medical interventions fail to control intracranial pressure, decompressive craniectomy to prevent herniation may be considered. This surgery addresses a physiological problem (refractory elevation of intracranial pressure) and has a proven benefit in the management of . . .

Sulfonylurea-receptor-1(SUR1) and its associated transient-receptor-potential cation channel subfamily-M (TRPM4) channel are key contributors to cerebral edema and intracranial hypertension in traumatic brain injury (TBI) and other neurological disorders. Channel inhibition by glyburide is clinically promising. ABCC8 (encoding SUR1) single-nucleotide polymorphisms (SNPs) are reported as predictors of raised intracranial pressure (ICP). This project evaluated whether TRPM4 SNPs predicted ICP and TBI outcome. DNA was extracted from 435 consecutively enrolled severe TBI patients. Without a priori selection, all 11 TRPM4 SNPs available on the multiplex platform (Illumina:Human-Core-Exome v1.0) were genotyped spanning the 25 exon gene. A total of 385 patients were analyzed after quality control. Outcomes included ICP and 6 month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modeling, and functional predictions were determined using established software programs. rs8104571 (intron-20) and rs150391806 (exon-24) were predictors of ICP. rs8104571 heterozygotes predicted higher average ICP (β = 10.3 mm Hg, p = 0.00000029), peak ICP (β = 19.6 mm Hg, p = 0.0007), and proportion ICP >25 mm Hg (β = 0.16 p = 0.004). rs150391806 heterozygotes had higher mean (β = 7.2 mm Hg, p = 0.042) and peak (β = 28.9 mm Hg, p = 0.0015) ICPs. rs8104571, rs150391806, and 34 associated proxy SNPs in linkage-disequilibrium clustered downstream. This region encodes TRPM4's channel pore and a region postulated to juxtapose SUR1 sequences encoded by an ABCC8 DNA segment containing previously identified relevant SNPs. There was an interaction effect on ICP between rs8104571 and a cluster of predictive ABCC8 SNPs (rs2237982, rs2283261, rs11024286). Although not significant in univariable or a basic multivariable model, in an expanded model additionally accounting for injury pattern, computed tomographic (CT) appearance, and intracranial hypertension, heterozygous rs8104571 was associated with favorable 6 month GOS (odds ratio [OR] = 16.7, p = 0.007951). This trend persisted in a survivor-only subcohort (OR = 20.67, p = 0.0168). In this cohort, two TRPM4 SNPs predicted increased ICP with large effect sizes. Both clustered downstream, spanning a region encoding the channel pore and interacting with SUR1. If validated, this may guide risk stratification and eventually inform treatment-responder classification for SUR1-TRPM4 inhibition in TBI. Larger studies are warranted.

Objective ABCC8 encodes sulfonylurea receptor 1, a key regulatory protein of cerebral oedema in many neurological disorders including traumatic brain injury (TBI). Sulfonylurea-receptor-1 inhibition has been promising in ameliorating cerebral oedema in clinical trials. We evaluated whether ABCC8 tag single-nucleotide polymorphisms predicted oedema and outcome in TBI.MethodsDNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. ABCC8 tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r2>0.8, minor-allele frequency >0.20) and sequenced (iPlex-Gold, MassArray). Outcomes included radiographic oedema, intracranial pressure (ICP) and 3-month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modelling, amino acid topology and functional predictions were determined using established software programs.ResultsWild-type rs7105832 and rs2237982 alleles and genotypes were associated with lower average ICP (β=−2.91, p=0.001; β=−2.28, p=0.003) and decreased radiographic oedema (OR 0.42, p=0.012; OR 0.52, p=0.017). Wild-type rs2237982 also increased favourable 3-month GOS (OR 2.45, p=0.006); this was partially mediated by oedema (p=0.03). Different polymorphisms predicted 3-month outcome: variant rs11024286 increased (OR 1.84, p=0.006) and wild-type rs4148622 decreased (OR 0.40, p=0.01) the odds of favourable outcome. Significant tag and concordant proxy SNPs regionally span introns/exons 2–15 of the 39-exon gene.ConclusionsThis study identifies four ABCC8 tag SNPs associated with cerebral oedema and/or outcome in TBI, tagging a region including 33 polymorphisms. In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk. Different variant polymorphisms were associated with favourable outcome, potentially suggesting distinct mechanisms. Significant polymorphisms spatially clustered flanking exons encoding the sulfonylurea receptor site and transmembrane domain 0/loop 0 (juxtaposing the channel pore/binding site). This, if validated, may help build a foundation for developing future strategies that may guide individualised care, treatment response, prognosis and patient selection for clinical trials.

Background Numerous trials have addressed intracranial pressure (ICP) management in neurocritical care. However, identifying its harmful thresholds and controlling ICP remain challenging in terms of improving outcomes. Evidence suggests that an individualized approach is necessary for establishing tolerance limits for ICP, incorporating factors such as ICP waveform (ICPW) or pulse morphology along with additional data provided by other invasive (e.g., brain oximetry) and noninvasive monitoring (NIM) methods (e.g., transcranial Doppler, optic nerve sheath diameter ultrasound, and pupillometry). This study aims to assess current ICP monitoring practices among experienced clinicians and explore whether guidelines should incorporate ancillary parameters from NIM and ICPW in future updates. Methods We conducted a survey among experienced professionals involved in researching and managing patients with severe injury across low-middle-income countries (LMICs) and high-income countries (HICs). We sought their insights on ICP monitoring, particularly focusing on the impact of NIM and ICPW in various clinical scenarios. Results From October to December 2023, 109 professionals from the Americas and Europe participated in the survey, evenly distributed between LMIC and HIC. When ICP ranged from 22 to 25 mm Hg, 62.3% of respondents were open to considering additional information, such as ICPW and other monitoring techniques, before adjusting therapy intensity levels. Moreover, 77% of respondents were inclined to reassess patients with ICP in the 18–22 mm Hg range, potentially escalating therapy intensity levels with the support of ICPW and NIM. Differences emerged between LMIC and HIC participants, with more LMIC respondents preferring arterial blood pressure transducer leveling at the heart and endorsing the use of NIM techniques and ICPW as ancillary information. Conclusions Experienced clinicians tend to personalize ICP management, emphasizing the importance of considering various monitoring techniques. ICPW and noninvasive techniques, particularly in LMIC settings, warrant further exploration and could potentially enhance individualized patient care. The study suggests updating guidelines to include these additional components for a more personalized approach to ICP management.

Background Both seizures and spreading depolarizations (SDs) are commonly detected using electrocorticography (ECoG) after severe traumatic brain injury (TBI). A close relationship between seizures and SDs has been described, but the implications of detecting either or both remain unclear. We sought to characterize the relationship between these two phenomena and their clinical significance. Methods We performed a post hoc analysis of a prospective observational clinical study of patients with severe TBI requiring neurosurgery at five academic neurotrauma centers. A subdural electrode array was placed intraoperatively and ECoG was recorded during intensive care. SDs, seizures, and high-frequency background characteristics were quantified offline using published standards and terminology. The primary outcome was the Glasgow Outcome Scale-Extended score at 6 months post injury. Results There were 138 patients with valid ECoG recordings; the mean age was 47 ± 19 years, and 104 (75%) were men. Overall, 2,219 ECoG-detected seizures occurred in 38 of 138 (28%) patients in a bimodal pattern, with peak incidences at 1.7–1.8 days and 3.8–4.0 days post injury. Seizures detected on scalp electroencephalography (EEG) were diagnosed by standard clinical care in only 18 of 138 (13%). Of 15 patients with ECoG-detected seizures and contemporaneous scalp EEG, seven (47%) had no definite scalp EEG correlate. ECoG-detected seizures were significantly associated with the severity and number of SDs, which occurred in 83 of 138 (60%) of patients. Temporal interactions were observed in 17 of 24 (70.8%) patients with both ECoG-detected seizures and SDs. After controlling for known prognostic covariates and the presence of SDs, seizures detected on either ECoG or scalp EEG did not have an independent association with 6-month functional outcome but portended worse outcome among those with clustered or isoelectric SDs. Conclusions In patients with severe TBI requiring neurosurgery, seizures were half as common as SDs. Seizures would have gone undetected without ECoG monitoring in 20% of patients. Although seizures alone did not influence 6-month functional outcomes in this cohort, they were independently associated with electrographic worsening and a lack of motor improvement following surgery. Temporal interactions between ECoG-detected seizures and SDs were common and held prognostic implications. Together, seizures and SDs may occur along a dynamic continuum of factors critical to the development of secondary brain injury. ECoG provides information integral to the clinical management of patients with TBI.