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Background and ObjectiveNearly one-third of patients with severe traumatic brain injury (TBI) develop posttraumatic epilepsy (PTE). The relationship between PTE and long-term outcomes is unknown. We tested whether, after controlling for injury severity and age, PTE is associated with worse functional outcomes after severe TBI.MethodsWe performed a retrospective analysis of a prospective database of patients with severe TBI treated from 2002 through 2018 at a single level 1 trauma center. Glasgow Outcome Scale (GOS) was collected at 3, 6, 12, and 24 months postinjury. We used repeated-measures logistic regression predicting GOS, dichotomized as favorable (GOS 4–5) and unfavorable (GOS 1–3), and a separate logistic model predicting mortality at 2 years. We used predictors as defined by the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) base model (i.e., age, pupil reactivity, and GCS motor score), PTE status, and time.ResultsOf 392 patients who survived to discharge, 98 (25%) developed PTE. The proportion of patients with favorable outcomes at 3 months did not differ between those with and without PTE (23% [95% Confidence Interval [CI]: 15%–34%] vs 32% [95% CI: 27%–39%];p= 0.11) but was significantly lower at 6 (33% [95% CI: 23%–44%] vs 46%; [95% CI: 39%–52%]p= 0.03), 12 (41% [95% CI: 30%–52%] vs 54% [95% CI: 47%–61%];p= 0.03), and 24 months (40% [95% CI: 47%–61%] vs 55% [95% CI: 47%–63%];p= 0.04). This was driven by higher rates of GOS 2 (vegetative) and 3 (severe disability) outcomes in the PTE group. By 2 years, the incidence of GOS 2 or 3 was double in the PTE group (46% [95% CI: 34%–59%]) compared with that in the non-PTE group (21% [95% CI: 16%–28%];p< 0.001), while mortality was similar (14% [95% CI: 7%–25%] vs 23% [95% CI: 17%–30%];p= 0.28). In multivariate analysis, patients with PTE had lower odds of favorable outcome (odds radio [OR] 0.1; 95% CI: 0.1–0.4;p< 0.001), but not mortality (OR 0.9; 95% CI: 0.1–1.9;p= 0.46).DiscussionPosttraumatic epilepsy is associated with impaired recovery from severe TBI and poor functional outcomes. Early screening and treatment of PTE may improve patient outcomes.

Neurocritical care is a relatively young subspecialty that is rapidly coming into its own. As the neurocritical care community has expanded, the process of training and credentialing physicians in this growing field has undergone a rapid evolution. This article will review the history and current state of neurocritical care training and education, physician certification, and program accreditation in the United States within the larger context of critical care training across subspecialties.

This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.

Critical illness myopathy (CIM) and critical illness polyneuropathy (CIP) are common disorders associated with substantial morbidity. Electrodiagnostic studies (EDx) are effective in diagnosing CIM/CIP and identifying mimicking conditions. We surveyed intensive care unit (ICU) providers to better understand their approach to ICU-acquired weakness (ICU-AW) and the perceived utility of EDx.This was a single health system, Web-based survey of ICU providers.Survey responses were received from 52 providers with a response rate of 22.1%. Most providers were somewhat familiar with CIM/CIP and median perceived prevalence was 30-49%. The majority (92.3%) of providers had no standard evaluation approach for ICU-AW. Electrodiagnostic testing was commonly considered, but many providers obtained it infrequently in presumed CIM/CIP cases. Electrodiagnostic studies were used to rule out other causes of weakness or to confirm the diagnosis of CIM/CIP. Many providers ordered EDx within 1 wk of identifying weakness. Finally, EDx were overshadowed by personal experience as the most helpful management tool for ICU-AW.Overall, ICU providers perceive that CIM/CIP are commonly encountered, but they may not have a standard approach to evaluation. Clinical experience increased familiarity of ICU-AW and is central to management. EDx results are usually thought to be helpful, albeit not often ordered, and more study is needed to determine when implementation is of most assistance. Increasing education and developing institutional standards may lead to increased awareness and improved evaluation of CIM/CIP, but more study is needed to determine if algorithmic approaches would change patient outcomes.

Transcranial Doppler ultrasonography (TCD) is a portable, bedside, noninvasive diagnostic tool used for the real-time assessment of cerebral hemodynamics. Despite the evident utility of TCD and the ability of this technique to function as a stethoscope to the brain, its use has been limited to specialized centers because of the dearth of technical and clinical expertise required to acquire and interpret the cerebrovascular parameters. Additionally, the conventional pragmatic episodic TCD monitoring protocols lack dynamic real-time feedback to guide time-critical clinical interventions. Fortunately, with the recent advent of automated robotic TCD technology in conjunction with the automated software for TCD data processing, we now have the technology to automatically acquire TCD data and obtain clinically relevant information in real-time. By obviating the need for highly trained clinical personnel, this technology shows great promise toward a future of widespread noninvasive monitoring to guide clinical care in patients with acute brain injury.Here, we describe a proposal for a prospective observational multicenter clinical trial to evaluate the safety and feasibility of prolonged automated robotic TCD monitoring in patients with severe acute traumatic brain injury (TBI). We will enroll patients with severe non-penetrating TBI with concomitant invasive multimodal monitoring including, intracranial pressure, brain tissue oxygenation, and brain temperature monitoring as part of standard of care in centers with varying degrees of TCD availability and experience. Additionally, we propose to evaluate the correlation of pertinent TCD-based cerebral autoregulation indices such as the critical closing pressure, and the pressure reactivity index with the brain tissue oxygenation values obtained invasively.The overarching goal of this study is to establish safety and feasibility of prolonged automated TCD monitoring for patients with TBI in the intensive care unit and identify clinically meaningful and pragmatic noninvasive targets for future interventions.

In 2016, the National Academies of Science, Engineering and Medicine called for the development of a National Trauma Research Action Plan. The Department of Defense funded the Coalition for National Trauma Research to generate a comprehensive research agenda spanning the continuum of trauma and burn care. Given the public health burden of injuries to the central nervous system, neurotrauma was one of 11 panels formed to address this recommendation with a gap analysis and generation of high-priority research questions.We recruited interdisciplinary experts to identify gaps in the neurotrauma literature, generate research questions, and prioritize those questions using a consensus-driven Delphi survey approach. We conducted four Delphi rounds in which participants generated key research questions and then prioritized the importance of the questions on a 9-point Likert scale. Consensus was defined as 60% or greater of panelists agreeing on the priority category. We then coded research questions using an National Trauma Research Action Plan taxonomy of 118 research concepts, which were consistent across all 11 panels.Twenty-eight neurotrauma experts generated 675 research questions. Of these, 364 (53.9%) reached consensus, and 56 were determined to be high priority (15.4%), 303 were deemed to be medium priority (83.2%), and 5 were low priority (1.4%). The research topics were stratified into three groups-severe traumatic brain injury (TBI), mild TBI (mTBI), and spinal cord injury. The number of high-priority questions for each subtopic was 46 for severe TBI (19.7%), 3 for mTBI (4.3%) and 7 for SCI (11.7%).This Delphi gap analysis of neurotrauma research identified 56 high-priority research questions. There are clear areas of focus for severe TBI, mTBI, and spinal cord injury that will help guide investigators in future neurotrauma research. Funding agencies should consider these gaps when they prioritize future research.Diagnostic Test or Criteria, Level IV.

Neurologic conditions are often encountered in the general intensive care unit. This article will discuss some of the more common neurologic issues encountered and provide guidance in the assessment and management of these conditions.

BackgroundNoninvasive detection of spreading depolarizations (SD), as a potentially treatable mechanism of worsening brain injuries after traumatic brain injuries (TBI), has remained elusive. Current methods to detect SDs are based on intracranial recording, an invasive method with limited spatial coverage. Less invasive methods to diagnose SD are needed to improve generalizability and application of this emerging science and to guide worsening brain injury treatments. Here, we demonstrate, for the first time, a signal processing paradigm that can enable automated detection of SDs using noninvasive electroencephalography (EEG).MethodsBuilding on our previously developed WAVEFRONT algorithm, we have designed a novel automated SD detection method. This algorithm, with learnable parameters and improved velocity estimation, extracts and tracks propagating power depressions, as well as near-DC shifts using low-density EEG. This modified WAVEFRONT is robust to the amplitude outliers and non-propagating depressions on the scalp. We show the feasibility of detecting SD events (700 total SDs) in continuous, low-density scalp EEG recording (95±42.2 hours with 19 electrodes) acquired from 12 severe TBI patients who underwent decompressive hemicraniectomy (DHC) and intracranial EEG that could be used as a ground truth for event detection. We quantify the performance of WAVEFRONT in terms of SD detection accuracy, including true positive rate (TPR) and false positive rate (FPR), as well as the accuracy of estimating the frequency of SDs.ResultsWAVEFRONT achieves the best average validation accuracy of 74% TPR (with 95% confidence interval of 70.8%-76.7%), with less than 1.5% FPR using Delta band EEG. Preliminary evidence suggests that WAVEFRONT can achieve a very good performance (regression with R2 ≃0.71) in the estimation of SD frequencies.ConclusionsWe demonstrate feasibility and quantify the performance of noninvasive SD detection after severe TBI using an automated algorithm. WAVEFRONT can potentially be used for diagnosis and monitoring of worsening brain injuries to guide treatments by providing a measure of SD frequency. Extension of these results to patients with intact skulls requires further study.

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified. Supplementary Information The online version contains supplementary material available at 10.1007/s12028-021-01260-x.

Traumatic brain injury (TBI) remains one of the most fatal and debilitating conditions in the world. Current clinical management in severe TBI patients is mainly concerned with reducing secondary insults and optimizing the balance between substrate delivery and consumption. Over the past decades, multimodality monitoring has become more widely available, and clinical management protocols have been published that recommend potential interventions to correct pathophysiological derangements. Even while evidence from randomized clinical trials is still lacking for many of the recommended interventions, these protocols and algorithms can be useful to define a clear standard of therapy where novel interventions can be added or be compared to. Over the past decade, more attention has been paid to holistic management, in which hemodynamic, respiratory, inflammatory or coagulation disturbances are detected and treated accordingly. Considerable variability with regards to the trajectories of recovery exists. Even while most of the recovery occurs in the first months after TBI, substantial changes may still occur in a later phase. Neuroprognostication is challenging in these patients, where a risk of self-fulfilling prophecies is a matter of concern. The present article provides a comprehensive and practical review of the current best practice in clinical management and long-term outcomes of moderate to severe TBI in adult patients admitted to the intensive care unit.

New neuroprotective therapies for severe traumatic brain injury (TBI) have not translated from pre-clinical to clinical success. Numerous explanations have been suggested in both the pre-clinical and clinical arenas. Coverage of TBI in the lay press has reinvigorated interest, creating a golden age of TBI research with innovative strategies to circumvent roadblocks. We discuss the need for more robust therapies. We present concepts for traditional and novel approaches to defining therapeutic targets. We review lessons learned from the ongoing work of the pre-clinical drug and biomarker screening consortium Operation Brain Trauma Therapy and suggest ways to further enhance pre-clinical consortia. Biomarkers have emerged that empower choice and assessment of target engagement by candidate therapies. Drug combinations may be needed, and it may require moving beyond conventional drug therapies. Precision medicine may also link the right therapy to the right patient, including new approaches to TBI classification beyond the Glasgow Coma Scale or anatomical phenotyping-incorporating new genetic and physiologic approaches. Therapeutic breakthroughs may also come from alternative approaches in clinical investigation (comparative effectiveness, adaptive trial design, use of the electronic medical record, and big data). The full continuum of care must also be represented in translational studies, given the important clinical role of pre-hospital events, extracerebral insults in the intensive care unit, and rehabilitation. TBI research from concussion to coma can cross-pollinate and further advancement of new therapies. Misconceptions can stifle/misdirect TBI research and deserve special attention. Finally, we synthesize an approach to deliver therapeutic breakthroughs in this golden age of TBI research.

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 (PbtO(2)), and optimal MAP remain undefined. METHODS: C57BL/6 mice (n = 72) underwent controlled cortical impact followed by HS (MAP = 25–27 mmHg). Ipsilateral hippocampal PbtO(2) (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 (LR(60), WB(60), LR(70), WB(70)). Additional LR (10 ml/kg) was bolused every 5 min for MAP below target. RESULTS: LR requirements in WB(60) (7.2 ± 5.0 mL/kg) and WB(70) (28.3 ± 9.6 mL/kg) were markedly lower than in LR(60) (132.8 ± 5.8 mL/kg) or LR(70) (152.2 ± 4.8 mL/kg; all p < 0.001). WB(70) MAP (72.5 ± 2.9 mmHg) was higher than LR(70) (59.8 ± 4.0 mmHg, p < 0.001). WB(60) MAP (68.7 ± 4.6 mmHg) was higher than LR(60) (53.5 ± 3.2 mmHg, p < 0.001). PbtO(2) was higher in WB(60) (43.8 ± 11.6 mmHg) vs either LR(60) (25.9 ± 13.0 mmHg, p = 0.04) or LR(70) (24.1 ± 8.1 mmHg, p = 0.001). PbtO(2) in WB(70) (40.7 ± 8.8 mmHg) was higher than in LR(70) (p = 0.007). Despite higher MAP in WB(70) vs WB(60) (p = .002), PbtO(2) 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.

When the fourth edition of the Brain Trauma Foundation's Guidelines for the Management of Severe Traumatic Brain Injury were finalized in late 2016, it was known that the results of the RESCUEicp (Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension) randomized controlled trial of decompressive craniectomy would be public after the guidelines were released. The guideline authors decided to proceed with publication but to update the decompressive craniectomy recommendations later in the spirit of “living guidelines,” whereby topics are updated more frequently, and between new editions, when important new evidence is published. The update to the decompressive craniectomy chapter presented here integrates the findings of the RESCUEicp study as well as the recently published 12-mo outcome data from the DECRA (Decompressive Craniectomy in Patients With Severe Traumatic Brain Injury) trial. Incorporation of these publications into the body of evidence led to the generation of 3 new level-IIA recommendations; a fourth previously presented level-IIA recommendation remains valid and has been restated. To increase the utility of the recommendations, we added a new section entitled Incorporating the Evidence into Practice. This summary of expert opinion provides important context and addresses key issues for practitioners, which are intended to help the clinician utilize the available evidence and these recommendations. The full guideline can be found at: https://braintrauma.org/guidelines/guidelines-for-the-management-of-severe-tbi-4th-ed#/.

ObjectiveTo develop and demonstrate early feasibility of a goals-of-care decision aid for surrogates of patients who are critically ill with traumatic brain injury (ciTBI) that meets accepted international decision aid guidelines.MethodsWe developed the decision aid in 4 stages: (1) qualitative study of goals-of-care communication and decision needs of 36 stakeholders of ciTBI (surrogates and physicians), which informed (2) development of paper-based decision aid with iterative revisions after feedback from 52 stakeholders; (3) acceptability and usability testing in 18 neurologic intensive care unit (neuroICU) family members recruited from 2 neuroICU waiting rooms using validated scales; and (4) open-label, randomized controlled feasibility trial in surrogates of ciTBI. We performed an interim analysis of 16 surrogates of 12 consecutive patients who are ciTBI to confirm early feasibility of the study protocol and report recruitment, participation, and retention rates to date.ResultsThe resultant goals-of-care decision aid achieved excellent usability (median System Usability Scale 87.5 [possible range 0–100]) and acceptability (97% graded the tool's content as “good” or “excellent”). Early feasibility of the decision aid and the feasibility trial protocol was demonstrated by high rates of recruitment (73% consented), participation (100%), and retention (100% both after the goals-of-care clinician–family meeting and at 3 months) and complete data for the measurements of all secondary decision-related and behavioral outcomes to date.ConclusionsOur systematic development process resulted in a novel goals-of-care decision aid for surrogates of patients who are ciTBI with excellent usability, acceptability, and early feasibility in the neuroICU environment, and meets international decision aid standards. This methodology may be a development model for other decision aids in neurology to promote shared decision-making.

Background Acute treatment of cerebral edema and elevated intracranial pressure is a common issue in patients with neurological injury. Practical recommendations regarding selection and monitoring of therapies for initial management of cerebral edema for optimal efficacy and safety are generally lacking. This guideline evaluates the role of hyperosmolar agents (mannitol, HTS), corticosteroids, and selected non-pharmacologic therapies in the acute treatment of cerebral edema. Clinicians must be able to select appropriate therapies for initial cerebral edema management based on available evidence while balancing efficacy and safety. Methods The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacy to create a panel in 2017. The group generated 16 clinical questions related to initial management of cerebral edema in various neurological insults using the PICO format. A research librarian executed a comprehensive literature search through July 2018. The panel screened the identified articles for inclusion related to each specific PICO question and abstracted necessary information for pertinent publications. The panel used GRADE methodology to categorize the quality of evidence as high, moderate, low, or very low based on their confidence that the findings of each publication approximate the true effect of the therapy. Results The panel generated recommendations regarding initial management of cerebral edema in neurocritical care patients with subarachnoid hemorrhage, traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, bacterial meningitis, and hepatic encephalopathy. Conclusion The available evidence suggests hyperosmolar therapy may be helpful in reducing ICP elevations or cerebral edema in patients with SAH, TBI, AIS, ICH, and HE, although neurological outcomes do not appear to be affected. Corticosteroids appear to be helpful in reducing cerebral edema in patients with bacterial meningitis, but not ICH. Differences in therapeutic response and safety may exist between HTS and mannitol. The use of these agents in these critical clinical situations merits close monitoring for adverse effects. There is a dire need for high-quality research to better inform clinicians of the best options for individualized care of patients with cerebral edema.

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n= 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q&nbsp

Monitoring and optimisation of brain tissue oxygen tension (PbtO

ObjectiveTo determine whether telemedicine technology can be used to reliably determine the neurologic diagnosis of death (NDD) in patients with catastrophic brain injury (CBI).MethodsWe included a convenience sample of patients with CBI at a single academic medical center from November 2016 through June 2018. We simultaneously performed brain death evaluation at the bedside and remotely via telemedicine. Remote examiners were neurointensivists who were experienced and knowledgeable in the NDD. In addition to standard clinical examination, we used quantitative pupillometry to evaluate pupil size and reactivity. We determined the proportion of agreement for each NDD examination element and the overall diagnosis of brain death between bedside and remote examiners.ResultsTwenty-nine patients with mean age 46 ± 18 years underwent 30 paired NDD examinations. Twenty-eight (97%) patients met the NDD criteria and were pronounced dead. One patient did not meet the NDD criteria and died after withdrawal of life support. With the exception of qualitative assessment of pupillary reactivity, we observed excellent agreement (97%–100% across NDD examination elements) between bedside and remote examiners and 97% agreement on the overall diagnosis of brain death. Unlike qualitative pupillary assessment, quantitative pupillometry was consistently interpretable by remote examiners.ConclusionsOur results suggest that remote telemedicine technology can be used to verify the findings of bedside examiners performing NDD examinations when a pupillometer is used to assess pupillary reactivity. When performed by neurocritical care experts, the telemedicine NDD examination has potential to facilitate timely and accurate certification of brain death in patients with CBI.Classification of EvidenceThis study provides Class IV evidence on the concordance of neurologic diagnosis of death by telemedicine and bedside examiners.

The Fifth Neurocritical Care Research Network (NCRN) Conference held in Boca Raton, Florida, in September of 2018 was devoted to challenging the current status quo and examining the role of the Neurocritical Care Society (NCS) in driving the science and research of neurocritical care. The aim of this in-person meeting was to set the agenda for the NCS’s Neurocritical Care Research Central, which is the overall research arm of the society. Prior to the meeting, all 103 participants received educational content (book and seminar) on the ‘Blue Ocean Strategy®,’ a concept from the business world which aims to identify undiscovered and uncontested market space, and to brainstorm innovative ideas and methods with which to address current challenges in neurocritical care research. Three five-member working groups met at least four times by teleconference prior to the in-person meeting to prepare answers to a set of questions using the Blue Ocean Strategy concept as a platform. At the Fifth NCRN Conference, these groups presented to a five-member jury and all attendees for open discussion. The jury then developed a set of recommendations for NCS to consider in order to move neurocritical care research forward. We have summarized the topics discussed at the conference and put forward recommendations for the future direction of the NCRN and neurocritical care research in general.

Sulfonylurea-receptor-1(SUR1) and its associated transient-receptor-potential cation channel subfamily-M (TRPM4) channel are key contributors to cerebral edema and intracranial hypertensio...

BackgroundInhospital stroke (IHS) is associated with high morbidity and mortality, likely related to multiple factors, including delayed time to recognition, associated comorbidities, and initial care from non-stroke trained providers. We hypothesized that guided revision of a formalized ‘stroke code’ system can improve diagnosis and time to thrombolysis and thrombectomy.MethodsIHS activations occurring at a comprehensive stroke center between 2013 and 2016 were retrospectively analyzed to guide revisions of an established stroke code protocol to improve provider communication and time to imaging, reduce stroke mimic rate, and improve the use of parallel processing. After protocol implementation, we prospectively collected data between 2016 and 2017 for comparison with the pre-implementation group, including diagnostic accuracy and relevant time points (code call to examination, examination to imaging, and imaging to intervention). We report descriptive statistics for comparison of patient characteristics and time metrics (time to imaging and reperfusion after IHS activation). Multivariable regression analysis was performed to identify independent predictors of stroke mimics and time metrics.ResultsThere were 136 cases in the pre-implementation group and 69 in the post-implementation group. A reduction in stroke mimics (52% vs 33%, P=0.01) occurred after protocol initiation. Mean time to imaging after stroke code call was 7.6 min shorter (P=0.026) and mean time from imaging to acute reperfusion therapy was 45.7 vs 19.8 min (P=0.05) in the pre- versus the post-implementation group.ConclusionRevision of an existing IHS protocol was associated with a lower rate of stroke mimics, and a shorter time to intravenous and intra-arterial intervention.

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. 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. Preoperative volumes of subdural and subarachnoid hemorrhage, but not parenchymal damage, were significantly associated with the occurrence of SDs (P’s

Background Cefepime (FEP) induced neurotoxicity (NT) may have serious implications for patients (pts). Retrospective studies have employed variable definitions of NT, finding renal impairment and FEP trough concentrations (Cmin) > 20 mg/L as risk factors. Prospective studies comparing antibiotics have not been performed. Methods We conducted a prospective study of pts receiving FEP or meropenem (MEM) with neurologic evaluation and therapeutic drug monitoring (TDM). A NT advisory board (NTAB) was established to develop standardized definitions of possible, probable and definitive NT (Fig 1). Cases of potential NT were adjudicated by the NTAB who were blinded to study treatment. FEP and MEM midpoint and Cmin concentrations were measured at steady-state by validated methods. Results 127 patients were included (70 FEP, 57 MEM). Demographics and treatment characteristics were similar between groups (Fig 2); 63% were in the ICU. FEP and MEM Cmin varied from 1.9 – 140.5 and 0.6 – 31.3 mg/L, respectively. Median FEP Cmin and total exposures (AUC) were 23.1 mg/L and 347.6 hr*mg/L, respectively. Corresponding MEM values were 5.9 mg/L and 124.8 hr*mg/L, respectively. Cmin values were inversely correlated with renal function for both FEP and MEM (P< 0.001). Rates of possible, probable, or definitive NT were 10% and 5% for FEP and MEM, respectively (P=0.51; Fig 3). 16% and 3% of pts with FEP Cmin > or < 20 mg/L had NT, respectively (P=0.11; Fig 4). Median MEM Cmin were 12.3 and 5.4 mg/L among pts with and without NT, respectively (P=0.09; Fig 4). Rates of NT did not vary by infusion length or dose. FEP and MEM exposures were similar between patients with (17%) or without (83%) microbiologic recurrence due to the same pathogen. FEP was discontinued in 4 pts due to NT; no pts stopped MEM due to NT. Conclusion Our study is the first to evaluate FEP NT prospectively and compare rates of NT to pts receiving MEM. We established criteria that were applied by a blinded NTAB. In doing so we found rates of NT to be lower than previously reported and not statistically different between FEP and MEM. Cmin values were highly variable and associated with numerically, but not statistically higher rates of NT for both agents. These findings serve as the basis for larger, multicenter studies and justify use of routine TDM to limit NT among high-risk pts. Disclosures Brandon Smith, MD, PharmD, Shionogi (Consultant, Advisor or Review Panel member) Alexandra Urban, MD, Neuropace (Consultant) Ryan K. Shields, PharmD, MS, Shionogi (Consultant, Research Grant or Support)

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.

Coma and disordered consciousness are common manifestations of acute neurological conditions and are among the most pervasive and challenging aspects of treatment in neurocritical care. Gaps exist in patient assessment, outcome prognostication, and treatment directed specifically at improving consciousness and cognitive recovery. In 2019, the Neurocritical Care Society (NCS) launched the Curing Coma Campaign in order to address the "grand challenge" of improving the management of patients with coma and decreased consciousness. One of the first steps was to bring together a Scientific Advisory Council including coma scientists, neurointensivists, neurorehabilitationists, and implementation experts in order to address the current scientific landscape and begin to develop a framework on how to move forward. This manuscript describes the proceedings of the first Curing Coma Campaign Scientific Advisory Council meeting which occurred in conjunction with the NCS Annual Meeting in October 2019 in Vancouver. Specifically, three major pillars were identified which should be considered: endotyping of coma and disorders of consciousness, biomarkers, and proof-of-concept clinical trials. Each is summarized with regard to current approach, benefits to the patient, family, and clinicians, and next steps. Integration of these three pillars will be essential to the success of the Curing Coma Campaign as will expanding the "curing coma community" to ensure broad participation of clinicians, scientists, and patient advocates with the goal of identifying and implementing treatments to fundamentally improve the outcome of patients. ispartof: NEUROCRITICAL CARE vol:33 issue:1 pages:1-12 ispartof: location:United States status: published

Background Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place. Methods Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting. Results We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms. Conclusions These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference. Electronic supplementary material The online version of this article (10.1007/s00134-019-05900-x) contains supplementary material, which is available to authorized users.

Posttraumatic stress disorder (PTSD) co-occurring with mild traumatic brain injury (mTBI) is common in veterans. Worse clinical outcome in those with PTSD has been associated with decreased serum neurosteroid levels. Furthermore, decreased cortical thickness has been associated with both PTSD and mTBI. However, it is not known whether decreased neurosteroids are associated with decreased cortical thickness in PTSD co-occurring with mTBI. This study included 141 individuals divided into the following groups: ( a) mTBI group (n = 32 [10 female, 22 male] veterans with a history of mTBI); ( b) PTSD + mTBI group (n = 41 [6 female, 35 male] veterans with current PTSD with a history of mTBI); and ( c) control group (n = 68 [35 female, 33 male] control participants), which were acquired through the Injury and Traumatic Stress (INTRuST) Clinical Consortium. Subjects underwent clinical assessment, magnetic resonance imaging at 3 T, and serum neurosteroid quantifications of allopregnanolone (ALLO) and pregnenolone (PREGN). Group differences in cortical thickness and associations between serum neurosteroid levels and cortical thickness were investigated. Cortical thickness was decreased in the PTSD + mTBI group compared with the other groups. In the PTSD + mTBI group, decreased cortical thickness was also associated with lower serum ALLO (right superior frontal cortex) and lower serum PREGN (left middle temporal and right orbitofrontal cortex). Cortical thickness in the middle temporal and orbitofrontal cortex was associated with PTSD symptom severity. There were no significant associations between neurosteroids and cortical thickness in the mTBI or control groups. Decreased cortical thickness in individuals with PTSD + mTBI is associated with decreased serum neurosteroid levels and greater PTSD symptom severity. Causality is unclear. However, future studies might investigate whether treatment with neurosteroids could counteract stress-induced neural atrophy in PTSD + mTBI by potentially preserving cortical thickness.

Importance Advances in treatment of traumatic brain injury are hindered by the inability to monitor pathological mechanisms in individual patients for targeted neuroprotective treatment. Spreading depolarizations, a mechanism of lesion development in animal models, are a novel candidate for clinical monitoring in patients with brain trauma who need surgery. Objective To test the null hypothesis that spreading depolarizations are not associated with worse neurologic outcomes. Design, Setting, and Participants This prospective, observational, multicenter cohort study was conducted from February 2009 to August 2013 in 5 level 1 trauma centers. Consecutive patients who required neurological surgery for treatment of acute brain trauma and for whom research consent could be obtained were enrolled; participants were excluded because of technical problems in data quality, patient withdrawal, or loss to follow-up. Primary statistical analysis took place from April to December 2018. Evaluators of outcome assessments were blinded to other measures. Interventions A 6-contact electrode strip was placed on the brain surface during surgery for continuous electrocorticography during intensive care. Main Outcomes and Measures Electrocorticography was scored for depolarizations, following international consensus procedures. Six-month outcomes were assessed by the Glasgow Outcome Scale–Extended score. Results A total of 157 patients were initially enrolled; 19 were subsequently excluded. The 138 remaining patients (104 men [75%]; median [interquartile range] age, 45 [29-64] years) underwent a median (interquartile range) of 75.5 (42.2-117.1) hours of electrocorticography. A total of 2837 spreading depolarizations occurred in 83 of 138 patients (60.1% incidence) who, compared with patients who did not have spreading depolarizations, had lower prehospital systolic blood pressure levels (mean [SD], 133 [31] mm Hg vs 146 [33] mm Hg;P = .03), more traumatic subarachnoid hemorrhage (depolarization incidences of 17 of 37 [46%], 18 of 32 [56%], 22 of 33 [67%], and 23 of 30 patients [77%] for Morris-Marshall Grades 0, 1, 2, and 3/4, respectively;P = .047), and worse radiographic pathology (in 38 of 73 patients [52%] and 42 of 60 patients [70%] for Rotterdam Scores 2-4 vs 5-6, respectively;P = .04). Of patients with depolarizations, 32 of 83 (39%) had only sporadic events that induced cortical spreading depression of spontaneous electrical activity, whereas 51 of 83 patients (61%) exhibited temporal clusters of depolarizations (≥3 in a 2-hour span). Nearly half of those with clusters (23 of 51 [45%]) also had depolarizations in an electrically silent area of the cortex (isoelectric spreading depolarization). Patients with clusters did not improve in motor neurologic examinations from presurgery to postelectrocorticography, while other patients did improve. In multivariate ordinal regression adjusting for baseline prognostic variables, the occurrence of depolarization clusters had an odds ratio of 2.29 (95% CI, 1.13-4.65;P = .02) for worse outcomes. Conclusions and Relevance In this cohort study of patients with acute brain trauma, spreading depolarizations were predominant but heterogeneous and independently associated with poor neurologic recovery. Monitoring the occurrence of spreading depolarizations may identify patients most likely to benefit from targeted management strategies.

Mild TBI (mTBI) and posttraumatic stress disorder (PTSD) are independent risk factors for suicidal behaviour (SB). Further, co-occurring mTBI and PTSD increase one’s risk for negative health and psychiatric outcomes. However, little research has examined the role of comorbid mTBI and PTSD on suicide risk. The present study utilized data from the Injury and TRaUmatic STress (INTRuST) Consortium to examine the prevalence of suicidal ideation (SI) and behaviours among four groups: 1) comorbid mTBI+PTSD, 2) PTSD only, 3) mTBI only, and 4) healthy controls. Prevalence of lifetime SI, current SI, and lifetime SB for individuals with mTBI+PTSD was 40%, 25%, and 19%, respectively. Prevalence of lifetime SI, current SI, and lifetime SB for individuals with PTSD only was 29%, 11%, and 11%, respectively. Prevalence of lifetime SI, current SI, and lifetime SB for individuals with mTBI only was 14%, 1%, and 2%, respectively. Group comparisons showed that individuals with mTBI alone experienced elevated rates of lifetime SI compared to healthy controls. History of mTBI did not add significantly to risk for suicidal ideation and behaviour beyond what is accounted for by PTSD. Findings suggest that PTSD seems to be driving risk for suicidal behaviour.

Background Post–intensive care syndrome (PICS) is a constellation of new or worsening impairments in physical, mental, or cognitive abilities or a combination of these in individuals who have survived critical illness requiring intensive care. Purpose The 2 purposes of this systematic review were to identify the scope and magnitude of physical problems associated with PICS during the first year after critical illness and to use the World Health Organization's International Classification of Functioning, Disability and Health (ICF) framework to elucidate impairments of body functions and structures, activity limitations, and participation restrictions associated with PICS. Data Sources Ovid MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, CINAHL Plus with Full Text (EBSCO), Web of Science, and Embase were searched from inception until March 7, 2017. Study Selection Two reviewers screened titles, abstracts, and full text to independently determine study eligibility based on inclusion and exclusion criteria. Data Extraction Study methodological quality was assessed using the Newcastle–Ottawa Scale. Data describing study methods, design, and participant outcomes were extracted. Data Synthesis Fifteen studies were eligible for review. Within the first year following critical illness, people who had received intensive care experienced impairments in all 3 domains of the ICF (body functions and structures, activity limitations, and participation restrictions). These impairments included decreased pulmonary function, reduced strength of respiratory and limb muscles, reduced 6-minute walk test distance, reduced ability to perform activities of daily living and instrumental activities of daily living, and reduced ability to return to driving and paid employment. Limitations The inclusion of only 15 observational studies in this review may limit the generalizability of the findings. Conclusions During the first year following critical illness, individuals with PICS experienced physical impairments in all 3 domains of the ICF.

ObjectiveABCC8 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.

OBJECTIVE This manuscript describes the state of neurocritical care fellowship training, compares its written standards to those of other critical care fellowship programs, and discusses how programmatic oversight by the United Council for Neurological Subspecialties should evolve to meet American College of Graduate Medical Education standards. This review is a work product of the Society of Critical Care Medicine Neuroscience section and was reviewed and approved by the Council of the Society of Critical Care Medicine. DATA SOURCES We evaluated the published training criteria and requirements of American College of Graduate Medical Education Critical Care subspecialty fellowships programs of Internal Medicine, Surgery, and Anesthesia and compared them with the training criteria and required competencies for neurocritical care. STUDY SELECTION We have reviewed the published training standards from American College of Graduate Medical Education as well as the United Council for Neurologic Subspecialties subspecialty training documents and clarified the definition and responsibilities of an intensivist with reference to the Leapfrog Group, the National Quality Forum, and the Joint Commission. DATA EXTRACTION No data at present exist to test the concept of similarity across specialty fellowship critical care training programs. DATA SYNTHESIS Neurocritical care training differs in its exposure to clinical entities that are directly associated to other critical care subspecialties. However, the core critical care knowledge, procedural skills, and competencies standards for neurocritical care appears to be similar with some important differences compared with American College of Graduate Medical Education critical care training programs. CONCLUSIONS The United Council for Neurologic Subspecialties has developed a directed program development strategy to emulate American College of Graduate Medical Education standards with the goal to have standards that are similar or identical to American College of Graduate Medical Education standards.

Background Clinicians may have limited opportunities to perform neurological determination of death (NDD, or brain death) certification during their training. This study aimed to evaluate the level of resident exposure to the brain death exam at a large-volume donor hospital. Methods In March 2014, we adapted a dual-physician model for NDD certification at our institution to improve resident education regarding NDD. To evaluate the incidence of resident exposure, we collected examiner information from all brain death exams conducted between January 2014 and July 2015. Organ procurement, family authorization, and brain death intervals were also collected to evaluate the impact of NDD timeliness on organ donation. Results A total of 68 patients who met NDD criteria were included in this study. For these patients, 127 brain death exams were performed, 108 (85%) by a critical care attending physician or fellow, 9 (7%) by a neurology resident, and 7 (6%) by a neurosurgery resident. Exposure rates for neurology and neurosurgery residents were approximately 0.22 and 0.20 exams/resident/year, respectively. The median brain death interval between exams was 1.0 hours (interquartile range, 0.0–2.5) hours. Resident involvement, time between exams, and dual exams were all found to be nonsignificant correlates of organ authorization and family refusal. Conclusions Neurology and neurosurgery residents may be limited in their exposure to the brain death exam during training. High-volume donor hospitals may be able to complete 2 exams for NDD certification in a timely manner without detrimentally influencing organ authorization or family refusal rates.

Surrogate decision-makers (“surrogates”) and physicians of incapacitated patients have different views of prognosis and how it should be communicated, but this has not been investigated in neurocritically ill patients. We examined surrogates’ communication preferences and physicians’ practices during the outcome prognostication for critically ill traumatic brain injury (ciTBI) patients in two level-1 trauma centers and seven academic medical centers in the USA. We used qualitative content analysis and descriptive statistics of transcribed interviews to identify themes in surrogates (n = 16) and physicians (n = 20). The majority of surrogates (82%) preferred numeric estimates describing the patient’s prognosis, as they felt it would increase prognostic certainty, and limit the uncertainty perceived as frustrating. Conversely, 75% of the physicians reported intentionally omitting numeric estimates during prognostication meetings due to low confidence in family members’ abilities to appropriately interpret probabilities, worry about creating false hope, and distrust in the accuracy and data quality of existing TBI outcome models. Physicians felt that these models are for research only and should not be applied to individual patients. Surrogates valued compassion during prognostication discussions, and acceptance of their goals-of-care decision by clinicians. Physicians and surrogates agreed on avoiding false hope. We identified fundamental differences in the communication preferences of prognostic information between ciTBI patient surrogates and physicians. These findings inform the content of a future decision aid for goals-of-care discussions in ciTBI patients. If validated, these findings may have important implications for improving communication practices in the neurointensive care unit independent of whether a formal decision aid is used.