Validating the Fluctuating Mental Status Evaluation in Neurocritically Ill Patients With Acute Stroke.

OBJECTIVES: Neurocritically ill patients are at high risk for developing delirium, which can worsen the long-term outcomes of this vulnerable population. However, existing delirium assessment tools do not account for neurologic deficits that often interfere with conventional testing and are therefore unreliable in neurocritically ill patients. We aimed to determine the accuracy and predictive validity of the Fluctuating Mental Status Evaluation (FMSE), a novel delirium screening tool developed specifically for neurocritically ill patients. DESIGN: Prospective validation study. SETTING: Neurocritical care unit at an academic medical center. PATIENTS: One hundred thirty-nine neurocritically ill stroke patients (mean age, 63.9 [sd, 15.9], median National Institutes of Health Stroke Scale score 11 [interquartile range, 2-17]). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Expert raters performed daily Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-based delirium assessments, while paired FMSE assessments were performed by trained clinicians. We analyzed 717 total noncomatose days of paired assessments, of which 52% (n = 373) were rated by experts as days with delirium; 53% of subjects were delirious during one or more days. Compared with expert ratings, the overall accuracy of the FMSE was high (area under the curve [AUC], 0.85; 95% CI, 0.82-0.87). FMSE scores greater than or equal to 1 had 86% sensitivity and 74% specificity on a per-assessment basis, while scores greater than or equal to 2 had 70% sensitivity and 88% specificity. Accuracy remained high in patients with aphasia (FMSE ≥ 1: 82% sensitivity, 64% specificity; FMSE ≥ 2: 64% sensitivity, 84% specificity) and those with decreased arousal (FMSE ≥ 1: 87% sensitivity, 77% specificity; FMSE ≥ 2: 71% sensitivity, 90% specificity). Positive FMSE assessments also had excellent accuracy when predicting functional outcomes at discharge (AUC, 0.86 [95% CI, 0.79-0.93]) and 3 months (AUC, 0.85 [95% CI, 0.78-0.92]). CONCLUSIONS: In this validation study, we found that the FMSE was an accurate delirium screening tool in neurocritically ill stroke patients. FMSE scores greater than or equal to 1 indicate "possible" delirium and should be used when prioritizing sensitivity, whereas scores greater than or equal to 2 indicate "probable" delirium and should be used when prioritizing specificity.

Early Glasgow Coma Scale Score and Prediction of Traumatic Brain Injury: A Secondary Analysis of Three Harmonized Prehospital Randomized Clinical Trials.

OBJECTIVES: The prehospital prediction of the radiographic diagnosis of traumatic brain injury (TBI) in hemorrhagic shock patients has the potential to promote early therapeutic interventions. However, the identification of TBI is often challenging and prehospital tools remain limited. While the Glasgow Coma Scale (GCS) score is frequently used to assess the extent of impaired consciousness after injury, the utility of the GCS scores in the early prehospital phase of care to predict TBI in patients with severe injury and concomitant shock is poorly understood. METHODS: We performed a post-hoc, secondary analysis utilizing data derived from three randomized prehospital clinical trials: the Prehospital Air Medical Plasma trial (PAMPER), the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport trial (STAAMP), and the Pragmatic Prehospital Type O Whole Blood Early Resuscitation (PPOWER) trial. Patients were dichotomized into two cohorts based on the presence of TBI and then further stratified into three groups based on prehospital GCS score: GCS 3, GCS 4-12, and GCS 13-15. The association between prehospital GCS score and clinical documentation of TBI was assessed. RESULTS: A total of 1,490 enrolled patients were included in this analysis. The percentage of patients with documented TBI in those with a GCS 3 was 59.5, 42.4% in those with a GCS 4-12, and 11.8% in those with a GCS 13-15. The positive predictive value (PPV) of the prehospital GCS score for the diagnosis of TBI is low, with a GCS of 3 having only a 60% PPV. Hypotension and prehospital intubation are independent predictors of a low prehospital GCS. Decreasing prehospital GCS is strongly associated with higher incidence or mortality over time, irrespective of the diagnosis of TBI. CONCLUSIONS: The ability to accurately predict the presence of TBI in the prehospital phase of care is essential. The utility of the GCS scores in the early prehospital phase of care to predict TBI in patients with severe injury and concomitant shock is limited. The use of novel scoring systems and improved technology are needed to promote the accurate early diagnosis of TBI.

A Comprehensive Perspective on Intracranial Pressure Monitoring and Individualized Management in Neurocritical Care: Results of a Survey with Global Experts.

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.

The Relationship Between Seizures and Spreading Depolarizations in Patients with Severe Traumatic Brain Injury.

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.

How much oxygen for the injured brain - can invasive parenchymal catheters help?

PURPOSE OF REVIEW: Each year in the United States there are over 2.5 million visits to emergency departments for traumatic brain injury (TBI), 300,000 hospitalizations, and 50,000 deaths. TBI initiates a complex cascade of events which can lead to significant secondary brain damage. Great interest exists in directly measuring cerebral oxygen delivery and demand after TBI to prevent this secondary injury. Several invasive, catheter-based devices are now available which directly monitor the partial pressure of oxygen in brain tissue (PbtO2), yet significant equipoise exists regarding their clinical use in severe TBI. RECENT FINDINGS: There are currently three ongoing multicenter randomized controlled trials studying the use of PbtO2 monitoring in severe TBI: BOOST-3, OXY-TC, and BONANZA. All three have similar inclusion/exclusion criteria, treatment protocols, and outcome measures. Despite mixed existing evidence, use of PbtO2 is already making its way into new TBI guidelines such as the recent Seattle International Brain Injury Consensus Conference. Analysis of high-fidelity data from multimodal monitoring, however, suggests that PbtO2 may only be one piece of the puzzle in severe TBI. SUMMARY: While current evidence regarding the use of PbtO2 remains mixed, three ongoing clinical trials are expected to definitively answer the question of what role PbtO2 monitoring plays in severe TBI.

Multifaceted Benefit of Whole Blood Versus Lactated Ringer's Resuscitation After Traumatic Brain Injury and Hemorrhagic Shock in Mice.

BACKGROUND: Despite increasing use in hemorrhagic shock (HS), whole blood (WB) resuscitation for polytrauma with traumatic brain injury (TBI) is largely unexplored. Current TBI guidelines recommend crystalloid for prehospital resuscitation. Although WB outperforms lactated Ringer's (LR) in increasing mean arterial pressure (MAP) in TBI + HS models, effects on brain tissue oxygenation (PbtO2), and optimal MAP remain undefined. METHODS: C57BL/6 mice (n = 72) underwent controlled cortical impact followed by HS (MAP = 25-27 mmHg). Ipsilateral hippocampal PbtO2 (n = 40) was measured by microelectrode. Mice were assigned to four groups (n = 18/group) for "prehospital" resuscitation (90 min) with LR or autologous WB, and target MAPs of 60 or 70 mmHg (LR60, WB60, LR70, WB70). Additional LR (10 ml/kg) was bolused every 5 min for MAP below target. RESULTS: LR requirements in WB60 (7.2 ± 5.0 mL/kg) and WB70 (28.3 ± 9.6 mL/kg) were markedly lower than in LR60 (132.8 ± 5.8 mL/kg) or LR70 (152.2 ± 4.8 mL/kg; all p < 0.001). WB70 MAP (72.5 ± 2.9 mmHg) was higher than LR70 (59.8 ± 4.0 mmHg, p < 0.001). WB60 MAP (68.7 ± 4.6 mmHg) was higher than LR60 (53.5 ± 3.2 mmHg, p < 0.001). PbtO2 was higher in WB60 (43.8 ± 11.6 mmHg) vs either LR60 (25.9 ± 13.0 mmHg, p = 0.04) or LR70 (24.1 ± 8.1 mmHg, p = 0.001). PbtO2 in WB70 (40.7 ± 8.8 mmHg) was higher than in LR70 (p = 0.007). Despite higher MAP in WB70 vs WB60 (p = .002), PbtO2 was similar. CONCLUSION: WB resuscitation after TBI + HS results in robust improvements in brain oxygenation while minimizing fluid volume when compared to standard LR resuscitation. WB resuscitation may allow for a lower prehospital MAP without compromising brain oxygenation when compared to LR resuscitation. Further studies evaluating the effects of these physiologic benefits on outcome after TBI with HS are warranted, to eventually inform clinical trials.

Neurostereologic Lesion Volumes and Spreading Depolarizations in Severe Traumatic Brain Injury Patients: A Pilot Study.

BACKGROUND: Spreading depolarizations (SDs) occur in 50-60% of patients after surgical treatment of severe traumatic brain injury (TBI) and are independently associated with unfavorable outcomes. Here we performed a pilot study to examine the relationship between SDs and various types of intracranial lesions, progression of parenchymal damage, and outcomes. METHODS: In a multicenter study, fifty patients (76% male; median age 40) were monitored for SD by continuous electrocorticography (ECoG; median duration 79 h) following surgical treatment of severe TBI. Volumes of hemorrhage and parenchymal damage were estimated using unbiased stereologic assessment of preoperative, postoperative, and post-ECoG serial computed tomography (CT) studies. Neurologic outcomes were assessed at 6 months by the Glasgow Outcome Scale-Extended. RESULTS: Preoperative volumes of subdural and subarachnoid hemorrhage, but not parenchymal damage, were significantly associated with the occurrence of SDs (P's < 0.05). Parenchymal damage increased significantly (median 34 ml [Interquartile range (IQR) - 2, 74]) over 7 (5, 8) days from preoperative to post-ECoG CT studies. Patients with and without SDs did not differ in extent of parenchymal damage increase [47 ml (3, 101) vs. 30 ml (- 2, 50), P = 0.27], but those exhibiting the isoelectric subtype of SDs had greater initial parenchymal damage and greater increases than other patients (P's < 0.05). Patients with temporal clusters of SDs (≥ 3 in 2 h; n = 10 patients), which included those with isoelectric SDs, had worse outcomes than those without clusters (P = 0.03), and parenchymal damage expansion also correlated with worse outcomes (P = 0.01). In multivariate regression with imputation, both clusters and lesion expansion were significant outcome predictors. CONCLUSIONS: These results suggest that subarachnoid and subdural blood are important primary injury factors in provoking SDs and that clustered SDs and parenchymal lesion expansion contribute independently to worse patient outcomes. These results warrant future prospective studies using detailed quantification of TBI lesion types to better understand the relationship between anatomic and physiologic measures of secondary injury.

Intracranial Pressure Trajectories: A Novel Approach to Informing Severe Traumatic Brain Injury Phenotypes.

OBJECTIVES: Intracranial pressure in traumatic brain injury is dynamic and influenced by factors like injury patterns, treatments, and genetics. Existing studies use time invariant summary intracranial pressure measures thus potentially losing critical information about temporal trends. We identified longitudinal intracranial pressure trajectories in severe traumatic brain injury and evaluated whether they predicted outcome. We further interrogated the model to explore whether ABCC8 polymorphisms (a known cerebraledema regulator) differed across trajectory groups. DESIGN: Prospective observational cohort. SETTING: Single-center academic medical center. PATIENTS: Four-hundred four severe traumatic brain injury patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used group-based trajectory modeling to identify hourly intracranial pressure trajectories in days 0-5 post traumatic brain injury incorporating risk factor adjustment (age, sex, Glasgow Coma Scale 6score, craniectomy, primary hemorrhage pattern). We compared 6-month outcomes (Glasgow Outcome Scale, Disability Rating Scale, mortality) and ABCC8 tag-single-nucleotide polymorphisms associated with cerebral edema (rs2237982, rs7105832) across groups. Regression models determined whether trajectory groups predicted outcome. A six trajectory group model best fit the data, identifying cohorts differing in initial intracranial pressure, evolution, and number/proportion of spikes greater than 20 mm Hg. There were pattern differences in age, hemorrhage type, and craniectomy rates. ABCC8 polymorphisms differed across groups. GOS (p = 0.006), Disability Rating Scale (p = 0.001), mortality (p < 0.0001), and rs2237982 (p = 0.035) differed across groups. Unfavorable outcomes were surprisingly predicted by both low intracranial pressure trajectories and sustained intracranial hypertension. Intracranial pressure variability differed across groups (p < 0.001) and may reflect preserved/impaired intracranial elastance/compliance. CONCLUSIONS: We employed a novel approach investigating longitudinal/dynamic intracranial pressure patterns in traumatic brain injury. In a risk adjusted model, six groups were identified and predicted outcomes. If validated, trajectory modeling may be a first step toward developing a new, granular approach for intracranial pressure phenotyping in conjunction with other phenotyping tools like biomarkers and neuroimaging. This may be particularly relevant in light of changing traumatic brain injury demographics toward the elderly.

Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury.

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. METHODS: DNA 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. RESULTS: Wild-type rs7105832 and rs2237982 alleles and genotypes were associated with lower average ICP (ß=-2.91, p=0.001; ß=-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. CONCLUSIONS: This 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.

The Prevalence and Impact of Status Epilepticus Secondary to Intracerebral Hemorrhage: Results from the US Nationwide Inpatient Sample.

BACKGROUND: Status epilepticus (SE) has been identified as a predictor of morbidity and mortality in many acute brain injury patient populations. We aimed to assess the prevalence and impact of SE after intracerebral hemorrhage (ICH) in a large patient sample to overcome limitations in previous small patient sample studies. METHODS: We queried the Nationwide Inpatient Sample for patients admitted for ICH from 1999 to 2011, excluding patients with other acute brain injuries. Patients were stratified into SE diagnosis and no SE diagnosis cohorts. We identified independent risk factors for SE and assessed the impact of SE on morbidity and mortality with multivariable logistic regression models. Logistic regression was used to evaluate the trend in SE diagnoses over time as well. RESULTS: SE was associated with significantly increased odds of both mortality and morbidity (odds ratios (OR) 1.18 [confidence intervals (CI) 1.01-1.39], and OR 1.53 [CI 1.22-1.91], respectively). Risk factors for SE included female sex (OR 1.17 [CI 1.01-1.35]), categorical van Walraven score (vWr 5-14: OR 1.68 [CI 1.41-2.01]; vWr > 14: OR 3.77 [CI 2.98-4.76]), sepsis (OR 2.06 [CI 1.58-2.68]), and encephalopathy (OR 3.14 [CI 2.49-3.96]). Age was found to be associated with reduced odds of SE (OR 0.97 [CI 0.97-0.97]). From 1999 to 2011, prevalence of SE diagnosis increased from 0.25 to 0.61% (p < 0.001). Factors associated with SE were female sex, medium and high risk vWr score, sepsis, and encephalopathy. Independent predictors associated with increased mortality from SE were increased age, pneumonia, myocardial infarction, cardiac arrest, and sepsis. CONCLUSIONS: SE is a significant, likely underdiagnosed, predictor of morbidity and mortality after ICH. Future studies are necessary to better identify which patients are at highest risk of SE to guide resource utilization.

Sulfonylurea Receptor-1: A Novel Biomarker for Cerebral Edema in Severe Traumatic Brain Injury.

OBJECTIVES: Cerebral edema is a key poor prognosticator in traumatic brain injury. There are no biomarkers identifying patients at-risk, or guiding mechanistically-precise therapies. Sulfonylurea receptor-1-transient receptor potential cation channel M4 is upregulated only after brain injury, causing edema in animal studies. We hypothesized that sulfonylurea receptor-1 is measurable in human cerebrospinal fluid after severe traumatic brain injury and is an informative biomarker of edema and outcome. DESIGN: A total of 119 cerebrospinal fluid samples were collected from 28 severe traumatic brain injury patients. Samples were retrieved at 12, 24, 48, 72 hours and before external ventricular drain removal. Fifteen control samples were obtained from patients with normal pressure hydrocephalus. Sulfonylurea receptor- 1 was quantified by enzyme-linked immunosorbent assay. Outcomes included CT edema, intracranial pressure measurements, therapies targeting edema, and 3-month Glasgow Outcome Scale score. MAIN RESULTS: Sulfonylurea receptor-1 was present in all severe traumatic brain injury patients (mean = 3.54 ± 3.39 ng/mL, peak = 7.13 ± 6.09 ng/mL) but undetectable in all controls (p < 0.001). Mean and peak sulfonylurea receptor-1 was higher in patients with CT edema (4.96 ± 1.13 ng/mL vs 2.10 ± 0.34 ng/mL; p = 0.023). There was a temporal delay between peak sulfonylurea receptor-1 and peak intracranial pressure in 91.7% of patients with intracranial hypertension. There was no association between mean/peak sulfonylurea receptor-1 and mean/peak intracranial pressure, proportion of intracranial pressure greater than 20 mm Hg, use of edema-directed therapies, decompressive craniotomy, or 3-month Glasgow Outcome Scale. However, decreasing sulfonylurea receptor-1 trajectories between 48 and 72 hours were significantly associated with improved cerebral edema and clinical outcome. Area under the multivariate model receiver operating characteristic curve was 0.881. CONCLUSIONS: This is the first report quantifying human cerebrospinal fluid sulfonylurea receptor-1. Sulfonylurea receptor-1 was detected in severe traumatic brain injury, absent in controls, correlated with CT-edema and preceded peak intracranial pressure. Sulfonylurea receptor-1 trajectories between 48 and 72 hours were associated with outcome. Because a therapy inhibiting sulfonylurea receptor-1 is available, assessing cerebrospinal fluid sulfonylurea receptor-1 in larger studies is warranted to evaluate our exploratory findings regarding its diagnostic, and monitoring utility, as well as its potential to guide targeted therapies in traumatic brain injury and other diseases involving cerebral edema.

Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial.

OBJECTIVES: A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study. DESIGN: Randomized prospective clinical trial. SETTING: Ten ICUs in the United States. PATIENTS: One hundred nineteen severe traumatic brain injury patients. INTERVENTIONS: Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended. MEASUREMENTS AND MAIN RESULTS: A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy. CONCLUSIONS: Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation-directed treatment of severe traumatic brain injury is warranted.

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI.

OBJECTIVE: Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE. METHODS: DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy. RESULTS: Fourteen SNPs with minor allele frequency >0.2 were identified. Four SNPS rs2283261, rs3819521, rs2283258, and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR 2.45, p = 0.007; OR 2.95, p = 0.025; OR 3.00, p = 0.013), had higher mean (ß = 3.13, p = 0.000; ß = 2.95, p = 0.005; ß = 3.20, p = 0.008), and peak ICP (ß = 8.00, p = 0.001; ß = 7.64, p = 0.007; ß = 6.89, p = 0.034). The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR 0.47, p = 0.004). CONCLUSIONS: This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective-potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.

Group-Based Trajectory Modeling of Suppression Ratio After Cardiac Arrest.

BACKGROUND: Existing studies of quantitative electroencephalography (qEEG) as a prognostic tool after cardiac arrest (CA) use methods that ignore the longitudinal pattern of qEEG data, resulting in significant information loss and precluding analysis of clinically important temporal trends. We tested the utility of group-based trajectory modeling (GBTM) for qEEG classification, focusing on the specific example of suppression ratio (SR). METHODS: We included comatose CA patients hospitalized from April 2010 to October 2014, excluding CA from trauma or neurological catastrophe. We used Persyst®v12 to generate SR trends and used semi-quantitative methods to choose appropriate sampling and averaging strategies. We used GBTM to partition SR data into different trajectories and regression associate trajectories with outcome. We derived a multivariate logistic model using clinical variables without qEEG to predict survival, then added trajectories and/or non-longitudinal SR estimates, and assessed changes in model performance. RESULTS: Overall, 289 CA patients had ≥36 h of EEG yielding 10,404 h of data (mean age 57 years, 81 % arrested out-of-hospital, 33 % shockable rhythms, 31 % overall survival, 17 % discharged to home or acute rehabilitation). We identified 4 distinct SR trajectories associated with survival (62, 26, 12, and 0 %, P < 0.0001 across groups) and CPC (35, 10, 4, and 0 %, P < 0.0001 across groups). Adding trajectories significantly improved model performance compared to adding non-longitudinal data. CONCLUSIONS: Longitudinal analysis of continuous qEEG data using GBTM provides more predictive information than analysis of qEEG at single time-points after CA.

Spreading depression in continuous electroencephalography of brain trauma.

OBJECTIVE: Cortical spreading depolarizations are a pathophysiological mechanism and candidate target for advanced monitoring in acute brain injury. Here we investigated manifestations of spreading depolarization in continuous electroencephalography (EEG) as a broadly applicable, noninvasive method for neuromonitoring. METHODS: Eighteen patients requiring surgical treatment of traumatic brain injury were monitored by invasive electrocorticography (ECoG; subdural electrodes) and noninvasive scalp EEG during intensive care. Spreading depolarizations were first identified in subdural recordings, and EEG was then examined visually and quantitatively to identify correlates. RESULTS: A total of 455 spreading depolarizations occurred during 65.9 days of simultaneous ECoG/EEG monitoring. For 179 of 455 events (39%), depolarizations caused temporally isolated, transient depressions of spontaneous EEG amplitudes to 57% (median) of baseline power. Depressions lasted 21 minutes (median) and occurred as suppressions of high-amplitude delta activity present as a baseline pattern in the injured hemisphere. For 62 of 179 (35%) events, isolated depressions showed a clear spread of depression between EEG channels with delays of 17 minutes (median), sometimes spanning the entire hemisphere. A further 188 of 455 (41%) depolarizations were associated with continuous EEG depression that lasted hours to days due to ongoing depolarizations. Depolarizations were also evidenced in EEG as shifts in direct current potentials. INTERPRETATION: Leão's spreading depression can be observed in clinically standard, continuous scalp EEG, and underlying depolarizations can spread widely across the injured cerebral hemisphere. These results open the possibility of monitoring noninvasively a neuronal pathophysiological mechanism in a wide range of disorders including ischemic stroke, subarachnoid hemorrhage, and brain trauma, and suggest a novel application for continuous EEG.

Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma.

Cortical spreading depolarization causes a breakdown of electrochemical gradients following acute brain injury, and also elicits dynamic changes in regional cerebral blood flow that range from physiological neurovascular coupling (hyperaemia) to pathological inverse coupling (hypoperfusion). In this study, we determined whether pathological inverse neurovascular coupling occurred as a mechanism of secondary brain injury in 24 patients who underwent craniotomy for severe traumatic brain injury. After surgery, spreading depolarizations were monitored with subdural electrode strips and regional cerebral blood flow was measured with a parenchymal thermal diffusion probe. The status of cerebrovascular autoregulation was monitored as a correlation between blood pressure and regional cerebral blood flow. A total of 876 spreading depolarizations were recorded in 17 of 24 patients, but blood flow measurements were obtained for only 196 events because of technical limitations. Transient haemodynamic responses were observed in time-locked association with 82 of 196 (42%) spreading depolarizations in five patients. Spreading depolarizations induced only hyperaemic responses (794% increase) in one patient with intact cerebrovascular autoregulation; and only inverse responses (-24% decrease) in another patient with impaired autoregulation. In contrast, three patients exhibited dynamic changes in neurovascular coupling to depolarizations throughout the course of recordings. Severity of the pathological inverse response progressively increased (-14%, -29%, -79% decrease, P < 0.05) during progressive worsening of cerebrovascular autoregulation in one patient (Pearson coefficient 0.04, 0.14, 0.28, P < 0.05). A second patient showed transformation from physiological hyperaemic coupling (44% increase) to pathological inverse coupling (-30% decrease) (P < 0.05) coinciding with loss of autoregulation (Pearson coefficient 0.19 → 0.32, P < 0.05). The third patient exhibited a similar transformation in brain tissue oxygenation, a surrogate of blood flow, from physiologic hyperoxic responses (20% increase) to pathological hypoxic responses (-14% decrease, P < 0.05). Pathological inverse coupling was only observed with electrodes placed in or adjacent to evolving lesions. Overall, 31% of the pathological inverse responses occurred during ischaemia (<18 ml/100 g/min) thus exacerbating perfusion deficits. Average perfusion was significantly higher in patients with good 6-month outcomes (46.8 ± 6.5 ml/100 g/min) than those with poor outcomes (32.2 ± 3.7 ml/100 g/min, P < 0.05). These results establish inverse neurovascular coupling to spreading depolarization as a novel mechanism of secondary brain injury and suggest that cortical spreading depolarization, the neurovascular response, cerebrovascular autoregulation, and ischaemia are critical processes to monitor and target therapeutically in the management of acute brain injury.

Intermittent versus continuous cerebrospinal fluid drainage management in adult severe traumatic brain injury: assessment of intracranial pressure burden.

INTRODUCTION: There is clinical equipoise regarding whether neurointensive care unit management of external ventricular drains (EVD) in severe traumatic brain injury (TBI) should involve an open EVD, with continuous drainage of cerebrospinal fluid (CSF), versus a closed EVD, with intermittent opening as necessary to drain CSF. In a matched cohort design, we assessed the relative impact of continuous versus intermittent CSF drainage on intracranial pressure in the management of adult severe TBI. METHODS: Sixty-two severe TBI patients were assessed. Thirty-one patients managed by open EVD drainage were matched by age, sex, and injury severity (initial Glasgow Coma Scale (GCS) score) to 31 patients treated with a closed EVD drainage. Patients in the open EVD group also had a parenchymal intracranial pressure (ICP) monitor placed through an adjacent burr hole, allowing real-time recording of ICP. Hourly ICP and other pertinent data, such as length of stay in intensive care unit (LOS-ICU), Injury Severity Score, and survival status, were extracted from our prospective database. RESULTS: With age, injury severity (initial GCS score), and neurosurgical intervention adjusted for, there was a statistically significant difference of 5.66 mmHg in mean ICP (p < 0.0001) between the open and the closed EVD groups, with the closed EVD group exhibiting greater mean ICP. ICP burden (ICP ≥ 20 mmHg) was shown to be significantly higher in the intermittent EVD group (p = 0.0002) in comparison with the continuous EVD group. CONCLUSION: Continuous CSF drainage via an open EVD seemed to be associated with more effective ICP control in the management of adult severe TBI.

Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury.

Spreading depolarizations are waves of mass neuronal and glial depolarization that propagate across the injured human cortex. They can occur with depression of neuronal activity as spreading depressions or isoelectric spreading depolarizations on a background of absent or minimal electroencephalogram activity. Spreading depolarizations are characterized by the loss of neuronal ion homeostasis and are believed to damage functional neurons, leading to neuronal necrosis or neurological degeneration and poor outcome. Analgesics and sedatives influence activity-dependent neuronal ion homeostasis and therefore represent potential modulators of spreading depolarizations. In this exploratory retrospective international multicentre analysis, we investigated the influence of midazolam, propofol, fentanyl, sufentanil, ketamine and morphine on the occurrence of spreading depolarizations in 115 brain-injured patients. A surface electrode strip was placed on the cortex, and continuous electrocorticographical recordings were obtained. We used multivariable binary logistic regression to quantify associations between the investigated drugs and the hours of electrocorticographical recordings with and without spreading depolarizations or clusters of spreading depolarizations. We found that administration of ketamine was associated with a reduction of spreading depolarizations and spreading depolarization clusters (P < 0.05). Midazolam anaesthesia, in contrast, was associated with an increased number of spreading depolarization clusters (P < 0.05). By using a univariate odds ratio analysis, we also found a significant association between ketamine administration and reduced occurrence of isoelectric spreading depolarizations in patients suffering from traumatic brain injury, subarachnoid haemorrhage and malignant hemispheric stroke (P < 0.05). Our findings suggest that ketamine-or another N-methyl-d-aspartate receptor antagonist-may represent a viable treatment for patients at risk for spreading depolarizations. This hypothesis will be tested in a prospective study.

COSBID-M3: a platform for multimodal monitoring, data collection, and research in neurocritical care.

Neuromonitoring in patients with severe brain trauma and stroke is often limited to intracranial pressure (ICP); advanced neuroscience intensive care units may also monitor brain oxygenation (partial pressure of brain tissue oxygen, P(bt)O(2)), electroencephalogram (EEG), cerebral blood flow (CBF), or neurochemistry. For example, cortical spreading depolarizations (CSDs) recorded by electrocorticography (ECoG) are associated with delayed cerebral ischemia after subarachnoid hemorrhage and are an attractive target for novel therapeutic approaches. However, to better understand pathophysiologic relations and realize the potential of multimodal monitoring, a common platform for data collection and integration is needed. We have developed a multimodal system that integrates clinical, research, and imaging data into a single research and development (R&D) platform. Our system is adapted from the widely used BCI2000, a brain-computer interface tool which is written in the C++ language and supports over 20 data acquisition systems. It is optimized for real-time analysis of multimodal data using advanced time and frequency domain analyses and is extensible for research development using a combination of C++, MATLAB, and Python languages. Continuous streams of raw and processed data, including BP (blood pressure), ICP, PtiO2, CBF, ECoG, EEG, and patient video are stored in an open binary data format. Selected events identified in raw (e.g., ICP) or processed (e.g., CSD) measures are displayed graphically, can trigger alarms, or can be sent to researchers or clinicians via text message. For instance, algorithms for automated detection of CSD have been incorporated, and processed ECoG signals are projected onto three-dimensional (3D) brain models based on patient magnetic resonance imaging (MRI) and computed tomographic (CT) scans, allowing real-time correlation of pathoanatomy and cortical function. This platform will provide clinicians and researchers with an advanced tool to investigate pathophysiologic relationships and novel measures of cerebral status, as well as implement treatment algorithms based on such multimodal measures.