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Background: Inducing normothermia with surface cooling temperature modulating devices (TMDs) is cumbersome and often associated with significant shivering. We tested the safety and feasibility of a novel transnasal evaporative cooling device to induce and maintain normothermia in febrile patients following ischemic and hemorrhagic stroke., Methods: A single-center study utilizing the CoolStat® transnasal cooling device was used to achieve core temperature reduction in mechanically ventilated stroke patients with fever (T ≥ 38.3 C) refractory to acetaminophen by inducing an evaporative cooling energy exchange in the nasal turbinates thru a high flow of dehumidified air into the nasal cavity and out through the mouth. Continuous temperature measurements were obtained from tympanic and core (esophageal or bladder) temperature monitors. Safety assessments included continuous monitoring for hypertension, tachycardia, and raised intracranial pressure (when monitored). Otolaryngology (ENT) evaluations were monitored for any device-related nasal mucosal injury with a pre- and post-visual examination. Shivering was assessed every 30 min using the Bedside Shivering Assessment Scale (BSAS). Duration of device use was limited to 8 h, at which time patients were transitioned to routine care for temperature management., Results: Ten subjects (median age: 54 years, BMI: 32.5 kg/m 2 , 60% men) were enrolled with normothermia achieved in 90% of subjects. One subject did not achieve normothermia and was later refractory to other TMDs. Median baseline temperature was 38.5 ± 0.1 C, with a reduction noted by 4 h (38.5 ± 0.1 vs 37.3 ± 0.8, P < 0.001) and sustained at 8 h (38.5 ± 0.1 vs 37.1 ± 0.7, P = 0.001). Time to normothermia was 2.6 ± 1.9 h. The median BSAS was 0 (range 0-1) with only 4 episodes necessitating meperidine across 76 h of study monitoring. No treatment was discontinued due to safety concerns. ENT evaluations noted no device-related adverse findings., Conclusions: Inducing normothermia with a novel transnasal TMD appears to be safe, feasible and not associated with significant shivering. A multicenter trial testing the ability of the CoolStat to maintain normothermia for 24 h is currently underway.

Background: Temperature modulating devices (TMD) currently utilize core temperature measurements during targeted temperature management (TTM) that are currently limited to esophageal (Et), bladder (Bt), or rectal (Rt) temperatures. We assessed the ability of a continuous noninvasive temperature monitor to accurately approximate core temperature during TTM., Methods: All patients undergoing TTM using a gel pad surface TMD and an existing core temperature monitoring device were eligible for this study. Core and continuous noninvasive temperature monitoring values were simultaneously recorded for up to 72 h of TTM. The two sets of temperature data were downloaded from a clinical data acquisition storage system at 1-min intervals. The Bland-Altman method assessed agreement between the core and continuous noninvasive temperature monitor values, by measuring the mean difference (± 2 SD) between these values., Results: There were 20 subjects that underwent study between January 2018 and March 2018 (55% women, age: 57 ± 14 years old, BMI: 28.9 + 9.8 kg/m 2 , 100% mechanically ventilated). The comparison patient temperature source was predominantly esophageal (n = 10) followed by bladder (n = 5) or rectal (n = 5). There were a total of 999 h of paired patient temperature data from esophageal (50%), bladder (25%), and rectal (25%) temperatures. Bland-Altman analysis demonstrated good agreement with the superficial temperature monitor and core temperature measures in all patients overall, with a difference mean of 0.06 ± 0.39 C (P = 0.99) and no proportional bias noted (β =0.002, P = 0.917)., Conclusions: Continuous noninvasive temperature monitoring is a suitable alternative method for assessing core temperature during TTM. Future studies should focus on developing connectivity with a continuous noninvasive temperature monitor to approximate core temperature during TTM.

The genome-wide architecture of chromatin-associated proteins that maintains chromosome integrity and gene regulation is not well defined. Here we use chromatin immunoprecipitation, exonuclease digestion and DNA sequencing (ChIP-exo/seq) 1,2 to define this architecture in Saccharomyces cerevisiae. We identify 21 meta-assemblages consisting of roughly 400 different proteins that are related to DNA replication, centromeres, subtelomeres, transposons and transcription by RNA polymerase (Pol) I, II and III. Replication proteins engulf a nucleosome, centromeres lack a nucleosome, and repressive proteins encompass three nucleosomes at subtelomeric X-elements. We find that most promoters associated with Pol II evolved to lack a regulatory region, having only a core promoter. These constitutive promoters comprise a short nucleosome-free region (NFR) adjacent to a +1 nucleosome, which together bind the transcription-initiation factor TFIID to form a preinitiation complex. Positioned insulators protect core promoters from upstream events. A small fraction of promoters evolved an architecture for inducibility, whereby sequence-specific transcription factors (ssTFs) create a nucleosome-depleted region (NDR) that is distinct from an NFR. We describe structural interactions among ssTFs, their cognate cofactors and the genome. These interactions include the nucleosomal and transcriptional regulators RPD3-L, SAGA, NuA4, Tup1, Mediator and SWI-SNF. Surprisingly, we do not detect interactions between ssTFs and TFIID, suggesting that such interactions do not stably occur. Our model for gene induction involves ssTFs, cofactors and general factors such as TBP and TFIIB, but not TFIID. By contrast, constitutive transcription involves TFIID but not ssTFs engaged with their cofactors. From this, we define a highly integrated network of gene regulation by ssTFs.

Importance: Knowledge of differences in mild traumatic brain injury (mTBI) recovery by sex and age may inform individualized treatment of these patients., Objective: To identify sex-related differences in symptom recovery from mTBI; secondarily, to explore age differences within women, who demonstrate poorer outcomes after TBI., Design, Setting, and Participants: The prospective cohort study Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) recruited 2000 patients with mTBI from February 26, 2014, to July 3, 2018, and 299 patients with orthopedic trauma (who served as controls) from January 26, 2016, to July 27, 2018. Patients were recruited from 18 level I trauma centers and followed up for 12 months. Data were analyzed from August 19, 2020, to March 3, 2021., Exposures: Patients with mTBI (defined by a Glasgow Coma Scale score of 13-15) triaged to head computed tomography in 24 hours or less; patients with orthopedic trauma served as controls., Main Outcomes and Measures: Measured outcomes included (1) the Rivermead Post Concussion Symptoms Questionnaire (RPQ), a 16-item self-report scale that assesses postconcussion symptom severity over the past 7 days relative to preinjury; (2) the Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (PCL-5), a 20-item test that measures the severity of posttraumatic stress disorder symptoms; (3) the Patient Health Questionnaire-9 (PHQ-9), a 9-item scale that measures depression based on symptom frequency over the past 2 weeks; and (4) the Brief Symptom Inventory-18 (BSI-18), an 18-item scale of psychological distress (split into Depression and Anxiety subscales)., Results: A total of 2000 patients with mTBI (1331 men [67%; mean (SD) age, 41.0 (17.3) years; 1026 White (78%)] and 669 women [33%; mean (SD) age, 43.0 (18.5) years; 505 (76%) White]). After adjustment of multiple comparisons, significant TBI × sex interactions were observed for cognitive symptoms (B = 0.76; 5% false discovery rate-corrected P = .02) and somatic RPQ symptoms (B = 0.80; 5% false discovery rate-corrected P = .02), with worse symptoms in women with mTBI than men, but no sex difference in symptoms in control patients with orthopedic trauma. Within the female patients evaluated, there was a significant TBI × age interaction for somatic RPQ symptoms, which were worse in female patients with mTBI aged 35 to 49 years compared with those aged 17 to 34 years (B = 1.65; P = .02) or older than 50 years (B = 1.66; P = .02)., Conclusions and Relevance: This study found that women were more vulnerable than men to persistent mTBI-related cognitive and somatic symptoms, whereas no sex difference in symptom burden was seen after orthopedic injury. Postconcussion symptoms were also worse in women aged 35 to 49 years than in younger and older women, but further investigation is needed to corroborate these findings and to identify the mechanisms involved. Results suggest that individualized clinical management of mTBI should consider sex and age, as some women are especially predisposed to chronic postconcussion symptoms even 12 months after injury.

Importance: Heterogeneity across patients with traumatic brain injury (TBI) presents challenges for clinical care and intervention design. Identifying distinct clinical phenotypes of TBI soon after injury may inform patient selection for precision medicine clinical trials., Objective: To investigate whether distinct neurobehavioral phenotypes can be identified 2 weeks after TBI and to characterize the degree to which early neurobehavioral phenotypes are associated with 6-month outcomes., Design, Setting, and Participants: This prospective cohort study included patients presenting to 18 US level 1 trauma centers within 24 hours of TBI from 2014 to 2019 as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Data were analyzed from January 28, 2020, to January 11, 2021., Exposures: TBI., Main Outcomes and Measures: Latent profiles (LPs) were derived from common dimensions of neurobehavioral functioning at 2 weeks after injury, assessed through National Institutes of Health TBI Common Data Elements (ie, Brief Symptom Inventory-18, Patient Health Questionnaire-9 Depression checklist, Posttraumatic Stress Disorder Checklist for DSM-5, PROMIS Pain Intensity scale, Insomnia Severity Index, Rey Auditory Verbal Learning Test, Wechsler Adult Intelligence Scale-Fourth Edition Coding and Symbol Search subtests, Trail Making Test, and NIH Toolbox Cognitive Battery Pattern Comparison Processing Speed, Dimensional Change Card Sort, Flanker Inhibitory Control and Attention, and Picture Sequence Memory subtests). Six-month outcomes were the Satisfaction With Life Scale (SWLS), Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS), Glasgow Outcome Scale-Extended (GOSE), and Rivermead Post-Concussion Symptoms Questionnaire (RPQ)., Results: Among 1757 patients with TBI included, 1184 (67.4%) were men, and the mean (SD) age was 39.9 (17.0) years. LP analysis revealed 4 distinct neurobehavioral phenotypes at 2 weeks after injury: emotionally resilient (419 individuals [23.8%]), cognitively impaired (368 individuals [20.9%]), cognitively resilient (620 individuals [35.3%]), and neuropsychiatrically distressed (with cognitive weaknesses; 350 individuals [19.9%]). Adding LP group to models including demographic characteristics, medical history, Glasgow Coma Scale score, and other injury characteristics was associated with significantly improved estimation of association with 6-month outcome (GOSE R2 increase = 0.09-0.19; SWLS R2 increase = 0.12-0.22; QOLIBRI-OS R2 increase = 0.14-0.32; RPQ R2 = 0.13-0.34)., Conclusions and Relevance: In this cohort study of patients with TBI presenting to US level-1 trauma centers, qualitatively distinct profiles of symptoms and cognitive functioning were identified at 2 weeks after TBI. These distinct phenotypes may help optimize clinical decision-making regarding prognosis, as well as selection and stratification for randomized clinical trials.

Background: Patients who survive aneurysmal subarachnoid hemorrhage (aSAH) are at risk for delayed neurological deficits (DND) and cerebral infarction. In this exploratory cohort comparison analysis, we compared in-hospital outcomes of aSAH patients administered a low-dose intravenous heparin (LDIVH) infusion (12 U/kg/h) vs those administered standard subcutaneous heparin (SQH) prophylaxis for deep vein thrombosis (DVT; 5000 U, 3 × daily)., Objective: To assess the safety and efficacy of LDIVH in aSAH patients., Methods: We retrospectively analyzed 556 consecutive cases of aSAH patients whose aneurysm was secured by clipping or coiling at a single institution over a 10-yr period, including 233 administered the LDIVH protocol and 323 administered the SQH protocol. Radiological and outcome data were compared between the 2 cohorts using multivariable logistic regression and propensity score-based inverse probability of treatment weighting (IPTW)., Results: The unadjusted rate of cerebral infarction in the LDIVH cohort was half that in SQH cohort (9 vs 18%; P = .004). Multivariable logistic regression showed that patients in the LDIVH cohort were significantly less likely than those in the SQH cohort to have DND (odds ratio (OR) 0.53 [95% CI: 0.33, 0.85]) or cerebral infarction (OR 0.40 [95% CI: 0.23, 0.71]). Analysis following IPTW showed similar results. Rates of hemorrhagic complications, heparin-induced thrombocytopenia and DVT were not different between cohorts., Conclusion: This cohort comparison analysis suggests that LDIVH infusion may favorably influence the outcome of patients after aSAH. Prospective studies are required to further assess the benefit of LDIVH infusion in patients with aSAH., (Copyright © 2020 by the Congress of Neurological Surgeons.)

In multicellular eukaryotes, RNA polymerase (Pol) II pauses transcription ~30-50 bp after initiation. While the budding yeast Saccharomyces has its transcription mechanisms mostly conserved with other eukaryotes, it appears to lack this fundamental promoter-proximal pausing. However, we now report that nearly all yeast genes, including constitutive and inducible genes, manifest two distinct transcriptional stall sites that are brought on by acute environmental signaling (e.g., peroxide stress). Pol II first stalls at the pre-initiation stage before promoter clearance, but after DNA melting and factor acquisition, and may involve inhibited dephosphorylation. The second stall occurs at the +2 nucleosome. It acquires most, but not all, elongation factor interactions. Its regulation may include Bur1/Spt4/5. Our results suggest that a double Pol II stall is a mechanism to downregulate essentially all genes in concert., Competing Interests: Declaration of interests B.F.P. is an owner of and has a financial interest in Peconic, which uses the ChIP-exo technology (U.S. Patent 20100323361A1) implemented in this study and could potentially benefit from the outcomes of this research. All other authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Limited data exist on the effect of continuous renal replacement therapy (CRRT) methods on anti-epileptic drug pharmacokinetics (PK). This prospective practice-based PK study aims to assess the impact of continuous venovenous hemofiltration (CVVH), a modality of CRRT, on levetiracetam PK in critically ill patients and to derive individualized dosing recommendations. Eleven patients receiving oral or intravenous levetiracetam and CVVH in various intensive care units at a large academic medical center were enrolled to investigate the need for dosing adjustments. Prefilter, postfilter, and ultrafiltrate samples were obtained before dosing, after the completion of the infusion or 1-hour postoral dose, and up to 6 additional time points postinfusion or postoral administration. Patient-specific blood and ultrafiltrate flow rates and laboratory values were also collected at the time of sampling. The average sieving coefficient (SC) for levetiracetam was 0.89 ± 0.1, indicating high filter efficiency. Six of the 11 patients experienced concentrations outside the reported therapeutic range (12-46 mg/L). The average volume of distribution was 0.73 L/kg. CVVH clearance contributes a major fraction of the total levetiracetam clearance (36-73%) in neurocritically ill patients. The average bias and precision of the estimated vs. observed total clearance value was ~ 10.6% and 21.5%. Major dose determinants were identified to be SC and effluent flow rate. Patients with higher ultrafiltrate rates will have increased drug clearance and, therefore, will require higher doses in order to match exposures seen in patients with normal renal function., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society of Clinical Pharmacology and Therapeutics.)

Objective: To assess variables associated with decannulation in patients with traumatic brain injury (TBI)., Participants: 79 patients with TBI requiring tracheostomy and ICU admission from January 1 st to December 31 st , 2014., Design: Retrospective analysis., Measures: Patients decannulated prior to 90 days were compared with patients who remained cannulated. Two Cox Proportional Hazards models were used to predict decannulation using variables prior to tracheostomy and throughout hospitalization., Results: Median time to decannulation was 37 days (Interquartile Range [IQR] 29-67). Variables prior to tracheostomy associated with decannulation included diabetes (HR, 0.15; 95% CI, 0.03-0.84; p =.03), craniotomy (HR, 0.25; 95% CI, 0.06-1.02; p =.05) and acute kidney injury (AKI) (HR, 0.06; 95% CI, 0.01-0.48; p =.01). Variables present throughout hospitalization included age (HR, 1.12; 95% CI, 1.01-1.21; p =.03), ventilator days (HR, 0.74; 95% CI, 0.57-0.95; p =.02), reintubation (HR, 0.07; 95% CI, 0.01-0.64; p =.02), aspiration (HR, 0.01; 95% CI, 0.0-0.29, p =.01), craniotomy (HR, 0.004; 95% CI, 0.0-0.39; p =.02) and AKI (HR, 0.0; 95% CI, 0.0-0.21; p =.01)., Conclusion: The presence of diabetes, craniotomy and acute kidney injury may inform the conversation surrounding chances for decannulation prior to tracheostomy.

Background: Sentinel headache (SH) is often assumed to portend an increased risk of delayed cerebral ischemia (DCI) and aneurysm rebleeding. This study aimed to re-evaluate the associations between SH and aneurysm rebleeding, DCI, and outcome after SAH., Methods: We retrospectively analyzed 1102 patients with spontaneous SAH and available data regarding history of SH who were enrolled in the Columbia University SAH Outcomes Project between 1996 and 2009. Patients were asked whether they had experienced any episodes of acute, sudden-onset severe headache in the 2 weeks preceding the most recent bleeding event. DCI was defined as neurologic deterioration, infarction, or both due to vasospasm. Rebleeding was defined as the appearance of new hemorrhage on computed tomography. Outcome was assessed at 3 months by telephone interview using the modified Rankin Scale., Results: SH was reported in 152 (14%) of 1102 patients. There were no significant differences between patients with and without SH with regard to admission Hunt-Hess grade or modified Fisher Scale. There was also no difference with regard to the frequency of aneurysm rebleeding (10% vs. 8%, P = 0.42), DCI (18% vs, 20%, P = 0.64), moderate-or-severe angiographic vasospasm on follow-up angiography (51% vs. 56%, P = 0.43), highest recorded mean middle cerebral artery flow velocity on transcranial Doppler (134 versus 128 cm/s, P = 0.30), or the distribution of modified Rankin Scale scores at 3 months., Conclusions: A history of sentinel headache before the clinical diagnosis of SAH does not imply an increased risk of DCI or further rebleeding, and carries no prognostic significance., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Improved understanding of post-cardiac arrest syndrome and clinical practices such as targeted temperature management have led to improved mortality in this cohort. Attention has now been placed on development of tools to aid in predicting functional outcome in comatose cardiac arrest survivors. Current practice uses a multimodal approach including physical examination, neuroimaging, and electrophysiologic data, with a primary utility in predicting poor functional outcome. These modalities remain confounded by self-fulfilling prophecy and the withdrawal of life-sustaining therapies. To date, a reliable measure to predict good functional outcome has not been established or validated, but the use of quantitative somatosensory evoked potential (SSEP) shows potential for this use. MEDLINE and EMBASE search using words "Cardiac Arrest" and "SSEP," "Somato sensory evoked potentials," "qSSEP," "quantitative SSEP," "targeted temperature management in cardiac arrest" was conducted. Relevant recent studies on targeted temperature management in cardiac arrest, plus studies on SSEP in cardiac arrest in the setting of hypothermia and without hypothermia, were included. In addition, animal studies evaluating the role of different components of SSEP in cardiac arrest were reviewed. SSEP is a specific indicator of poor outcomes in post-cardiac arrest patients but lacks sensitivity and has not clinically been established to foresee good outcomes. Novel methods of analyzing quantitative SSEP (qSSEP) signals have shown potential to predict good outcomes in animal and human studies. In addition, qSSEP has potential to track cerebral recovery and guide treatment strategy in post-cardiac arrest patients. Lying beyond the current clinical practice of dichotomized absent/present N20 peaks, qSSEP has the potential to emerge as one of the earliest predictors of good outcome in comatose post-cardiac arrest patients. Validation of qSSEP markers in prospective studies to predict good and poor outcomes in the cardiac arrest population in the setting of hypothermia could advance care in cardiac arrest. It has the prospect to guide allocation of health care resources and reduce self-fulfilling prophecy.

Trypanosoma brucei CRK9 is an essential cyclin-dependent kinase for the parasite-specific mode of pre-mRNA processing. In trypanosomes, protein coding genes are arranged in directional arrays that are transcribed polycistronically, and individual mRNAs are generated by spliced leader trans-splicing and polyadenylation, processes that are functionally linked. Since CRK9 silencing caused a decline of mRNAs, a concomitant increase of unspliced pre-mRNAs and the disappearance of the trans-splicing Y structure intermediate, CRK9 is essential for the first step of splicing. CRK9 depletion also caused a loss of phosphorylation in RPB1, the largest subunit of RNA polymerase (pol) II. Here, we established cell lines that exclusively express analog-sensitive CRK9 (CRK9 AS ). Inhibition of CRK9 AS in these cells by the ATP-competitive inhibitor 1-NM-PP1 reproduced the splicing defects and proved that it is the CKR9 kinase activity that is required for pre-mRNA processing. Since defective trans-splicing was detected as early as 5 min after inhibitor addition, CRK9 presumably carries out reversible phosphorylation on the pre-mRNA processing machinery. Loss of RPB1 phosphorylation, however, took 12-24 hr. Surprisingly, RNA pol II-mediated RNA synthesis in 24 hr-treated cells was upregulated, indicating that, in contrast to other eukaryotes, RPB1 phosphorylation is not a prerequisite for transcription in trypanosomes., (© 2020 John Wiley & Sons Ltd.)

Competing Interests: Conflicts of interest: The authors declared no conflict of interest in preparation of this manuscript.

Introduction : Brain swelling due to edema formation is a major cause of neurological deterioration and death in patients with large hemispheric infarction (LHI) and severe traumatic brain injury (TBI), especially contusion-TBI. Preclinical studies have shown that SUR1-TRPM4 channels play a critical role in edema formation and brain swelling in LHI and TBI. Glibenclamide, a sulfonylurea drug and potent inhibitor of SUR1-TRPM4, was reformulated for intravenous injection, known as BIIB093. Areas covered : We discuss the findings from Phase 2 clinical trials of BIIB093 in patients with LHI (GAMES-Pilot and GAMES-RP) and from a small Phase 2 clinical trial in patients with TBI. For the GAMES trials, we review data on objective biological variables, adjudicated edema-related endpoints, functional outcomes, and mortality which, despite missing the primary endpoint, supported the initiation of a Phase 3 trial in LHI (CHARM). For the TBI trial, we review data on MRI measures of edema and the initiation of a Phase 2 trial in contusion-TBI (ASTRAL). Expert opinion : Emerging clinical data show that BIIB093 has the potential to transform our management of patients with LHI, contusion-TBI and other conditions in which swelling leads to neurological deterioration and death.

Importance: Most traumatic brain injuries (TBIs) are classified as mild (mTBI) based on admission Glasgow Coma Scale (GCS) scores of 13 to 15. The prevalence of persistent functional limitations for these patients is unclear., Objectives: To characterize the natural history of recovery of daily function following mTBI vs peripheral orthopedic traumatic injury in the first 12 months postinjury using data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study, and, using clinical computed tomographic (CT) scans, examine whether the presence (CT+) or absence (CT-) of acute intracranial findings in the mTBI group was associated with outcomes., Design, Setting, and Participants: TRACK-TBI, a cohort study of patients with mTBI presenting to US level I trauma centers, enrolled patients from February 26, 2014, to August 8, 2018, and followed up for 12 months. A total of 1453 patients at 11 level I trauma center emergency departments or inpatient units met inclusion criteria (ie, mTBI [n = 1154] or peripheral orthopedic traumatic injury [n = 299]) and were enrolled within 24 hours of injury; mTBI participants had admission GCS scores of 13 to 15 and clinical head CT scans. Patients with peripheral orthopedic trauma injury served as the control (OTC) group., Exposures: Participants with mTBI or OTC., Main Outcomes and Measures: The Glasgow Outcome Scale Extended (GOSE) scale score, reflecting injury-related functional limitations across broad life domains at 2 weeks and 3, 6, and 12 months postinjury was the primary outcome. The possible score range of the GOSE score is 1 (dead) to 8 (upper good recovery), with a score less than 8 indicating some degree of functional impairment., Results: Of the 1453 participants, 953 (65.6%) were men; mean (SD) age was 40.9 (17.1) years in the mTBI group and 40.9 (15.4) years in the OTC group. Most participants (mTBI, 87%; OTC, 93%) reported functional limitations (GOSE <8) at 2 weeks postinjury. At 12 months, the percentage of mTBI participants reporting functional limitations was 53% (95% CI, 49%-56%) vs 38% (95% CI, 30%-45%) for OTCs. A higher percentage of CT+ patients reported impairment (61%) compared with the mTBI CT- group (49%; relative risk [RR], 1.24; 95% CI, 1.08-1.43) and a higher percentage in the mTBI CT-group compared with the OTC group (RR, 1.28; 95% CI, 1.02-1.60)., Conclusions and Relevance: Most patients with mTBI presenting to US level I trauma centers report persistent, injury-related life difficulties at 1 year postinjury, suggesting the need for more systematic follow-up of patients with mTBI to provide treatments and reduce the risk of chronic problems after mTBI.

The purpose of the present study was to evaluate the impact of sleep disturbances on subsequent depressive symptomatology among a representative sample of patients following traumatic brain injury (TBI). Within a retrospective cohort design, our sample included 305 individuals from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot; NINDS-OD09-004) database. At 3-months post-TBI, symptoms of insomnia were reported by 34% of patients, and symptoms of hypersomnia were reported by 39% of patients. For the vast majority of individuals, sleep complaints were likely to persist through 6-month follow-up. Symptoms of hypersomnia but not insomnia at three months were associated with worsened depressive symptomatology at six months. These results highlight the importance of sleep disturbances in recovery from TBI and suggest targeted sleep treatments as a pathway to improve outcomes and quality of life following TBI.

Background: Data regarding who will require tracheostomy are lacking which may limit investigations into therapeutic effects of early tracheostomy., Methods: We performed an observational study of adult traumatic brain injury (TBI) patients requiring intensive care unit (ICU) admission for ≥ 72 h and mechanical ventilation for ≥ 24 h between January 2014 and December 2014 at a level 1 trauma center. Patients who had life-sustaining measures withdrawn were excluded. Multivariable logistic regression analyses were used to assess admission and inpatient factors associated with receiving a tracheostomy and to develop predictive models. Inpatient complications prior to day 7 were used to standardize data collection for patients with and without tracheostomy. Patients who received tracheostomy prior to day 7 were excluded from analysis., Results: In total, 209 patients (78% men, mean 48 years old, median Glasgow Coma Scale score (GCS) 8) met study criteria with tracheostomy performed in 94 (45%). Admission predictors of tracheostomy included GCS, chest tube, Injury Severity Score, and Marshall score. Inpatient factors associated with tracheostomy included the requirement for an external ventricular drain (EVD), number of operations, inpatient dialysis, aspiration, GCS on day 5, and reintubation. Multiple logistic regression analysis demonstrated that the number of operation room trips (adjusted odds ratio [AOR], 1.75; 95% CI, 1.04-2.97; P = 0.036), reintubation (AOR, 8.45; 95% CI, 1.91-37.44; P = .005), and placement of an EVD (AOR, 3.48; 95% CI, 1.27-9.58; P = .016) were independently associated with patients undergoing tracheostomy. Higher GCS on hospital day 5 (AOR, 0.52; 95% CI, 0.40-0.68; P < 0.001) was protective against tracheostomy. A model of inpatient variables only had a stronger association with tracheostomy than one with admission variables only (ROC AUC 0.93 vs 0.72, P < 0.001) and did not benefit from the addition of admission variables (ROC AUC 0.93 vs 0.92, P = 0.78)., Conclusion: Potentially modifiable inpatient factors have a stronger association with tracheostomy than do admission characteristics. Multicenter studies are needed to validate the results.

Importance: Traumatic brain injury (TBI) has been associated with adverse mental health outcomes, such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), but little is known about factors that modify risk for these psychiatric sequelae, particularly in the civilian sector., Objective: To ascertain prevalence of and risk factors for PTSD and MDD among patients evaluated in the emergency department for mild TBI (mTBI)., Design, Setting, and Participants: Prospective longitudinal cohort study (February 2014 to May 2018). Posttraumatic stress disorder and MDD symptoms were assessed using the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9 Item. Risk factors evaluated included preinjury and injury characteristics. Propensity score weights-adjusted multivariable logistic regression models were performed to assess associations with PTSD and MDD. A total of 1155 patients with mTBI (Glasgow Coma Scale score, 13-15) and 230 patients with nonhead orthopedic trauma injuries 17 years and older seen in 11 US hospitals with level 1 trauma centers were included in this study., Main Outcomes and Measures: Probable PTSD (PTSD Checklist for DSM-5 score, ≥33) and MDD (Patient Health Questionnaire-9 Item score, ≥15) at 3, 6, and 12 months postinjury., Results: Participants were 1155 patients (752 men [65.1%]; mean [SD] age, 40.5 [17.2] years) with mTBI and 230 patients (155 men [67.4%]; mean [SD] age, 40.4 [15.6] years) with nonhead orthopedic trauma injuries. Weights-adjusted prevalence of PTSD and/or MDD in the mTBI vs orthopedic trauma comparison groups at 3 months was 20.0% (SE, 1.4%) vs 8.7% (SE, 2.2%) (P < .001) and at 6 months was 21.2% (SE, 1.5%) vs 12.1% (SE, 3.2%) (P = .03). Risk factors for probable PTSD at 6 months after mTBI included less education (adjusted odds ratio, 0.89; 95% CI, 0.82-0.97 per year), being black (adjusted odds ratio, 5.11; 95% CI, 2.89-9.05), self-reported psychiatric history (adjusted odds ratio, 3.57; 95% CI, 2.09-6.09), and injury resulting from assault or other violence (adjusted odds ratio, 3.43; 95% CI, 1.56-7.54). Risk factors for probable MDD after mTBI were similar with the exception that cause of injury was not associated with increased risk., Conclusions and Relevance: After mTBI, some individuals, on the basis of education, race/ethnicity, history of mental health problems, and cause of injury were at substantially increased risk of PTSD and/or MDD. These findings should influence recognition of at-risk individuals and inform efforts at surveillance, follow-up, and intervention.

Background and Purpose: Current literature reports that half of critically ill patients are continued on broad-spectrum antibiotics beyond 72 hours despite no confirmed infection. The purpose of this retrospective study was to identify the incidence of and risk factors for prolonged empiric antimicrobial therapy (PEAT) in adult neurocritical care (NCC) patients treated for pneumonia, hypothesizing that NCC patients will have a higher incidence of PEAT., Methods: This is a retrospective chart review of adult NCC patients treated for pneumonia. Antibiotic therapy was classified as restrictive, definitive, or PEAT based on culture results and timing of discontinuation or de-escalation., Results: A total of 95 patients (median age: 57 years; 28.4% female; admission diagnosis: 73.7% cerebrovascular, 10.5% neuromuscular, and 15.8% seizure-related) were included in this study. Overall, 59% of antibiotic regimens were considered PEAT, with vancomycin and piperacillin/tazobactam being most commonly prescribed. Median duration of therapy was 6.8 days, with shorter duration in patients with negative culture results compared to those with positive culture results (6.1 days [interquartile range, IQR 4.0-8.3] vs 7.2 days [IQR 5.8-10.3], P < .05). On multivariable analysis, elevated baseline white blood cell count, meeting Centers for Disease Control criteria for pneumonia, and negative bacterial culture were significantly associated with PEAT., Conclusion: The incidence of prolonged empiric antibiotic use was high in the NCC population. Patients are at particular risk for PEAT if they have negative cultures. All but one patient did not meet criteria for central fever, highlighting the challenges in identifying fever etiology in the NCC population., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Regional cerebral oxygen saturation (rScO2) measured by near-infrared spectroscopy (NIRS) can be used to monitor brain oxygenation in extracorporeal membrane oxygenation (ECMO). ECMO patients that develop acute brain injuries (ABIs) are observed to have worse outcomes. We evaluated the association between rScO2 and ABI in venoarterial (VA) ECMO patients. Methods: We retrospectively reviewed prospectively-collected NIRS data from patients undergoing VA ECMO from April 2016 to October 2016. Baseline demographics, ECMO and clinical characteristics, cerebral oximetry data, neuroradiographic images, and functional outcomes were reviewed for each patient. rScO2 desaturations were defined as a >25% decline from baseline or an absolute value < 40% and quantified by frequency, duration, and area under the curve per hour of NIRS monitoring (AUC rate, rScO2 * min/h). The primary outcome was ABI, defined as abnormalities noted on brain computerized tomography (CT) or magnetic resonance imaging (MRI) obtained during or after ECMO therapy. Results: Eighteen of Twenty patients who underwent NIRS monitoring while on VA ECMO were included in analysis. Eleven patients (61%) experienced rScO2 desaturations. Patients with desaturations were more frequently female (73 vs. 14%, p = 0.05), had acute liver dysfunction (64 vs. 14%, p = 0.05), and higher peak total bilirubin (5.2 mg/dL vs. 1.4 mg/dL, p = 0.02). Six (33%) patients exhibited ABI, and had lower pre-ECMO Glasgow Coma Scale (GCS) scores (5 vs. 10, p = 0.03) and higher peak total bilirubin levels (7.3 vs. 1.4, p = 0.009). All ABI patients experienced rScO2 desaturation while 42% of patients without ABI experienced desaturation ( p = 0.04). ABI patients had higher AUC rates than non-ABI patients (right hemisphere: 5.7 vs. 0, p = 0.01, left hemisphere: 119 vs. 0, p = 0.06), more desaturation events (13 vs. 0, p = 0.05), longer desaturation duration (2:33 vs. 0, p = 0.002), and more severe desaturation events with rScO2 < 40 (9 vs. 0, p = 0.05). Patients with ABI had lower GCS scores (post-ECMO initiation) before care withdrawal or discharge than those without ABI (10 vs. 15, p = 0.02). Conclusions: The presence and burden of cerebral desaturations noted on NIRS cerebral oximetry are associated with secondary neurologic injury in adults undergoing VA ECMO.

A rapidly expanding scientific literature supports the frequent co-occurrence of sleep and circadian disturbances following mild traumatic brain injury (mTBI). Although many questions remain unanswered, the preponderance of evidence suggests that sleep and circadian disorders can result from mTBI. Among those with mTBI, sleep disturbances and clinical sleep and circadian disorders contribute to the morbidity and long-term sequelae across domains of functional outcomes and quality of life. Specifically, along with deterioration of neurocognitive performance, insufficient and disturbed sleep can precede, exacerbate, or perpetuate many of the other common sequelae of mTBI, including depression, post-traumatic stress disorder, and chronic pain. Further, sleep and mTBI share neurophysiologic and neuroanatomic mechanisms that likely bear directly on success of rehabilitation following mTBI. For these reasons, focus on disturbed sleep as a modifiable treatment target has high likelihood of improving outcomes in mTBI. Here, we review relevant literature and present a research agenda to 1) advance understanding of the reciprocal relationships between sleep and circadian factors and mTBI sequelae and 2) advance rapidly the development of sleep-related treatments in this population.

Background: Unsuccessful extubation is associated with increased intensive care unit and hospital length of stays, hospital costs, morbidity, and mortality. The most common cause of reintubation is laryngeal edema, often evidenced by postextubation stridor., Objective: To reduce the rates of postextubation stridor and reintubation in the neurocritical care unit at a large urban academic medical center., Methods: A clinical pathway was created to aid in detecting patients expected to experience postextubation stridor and to guide prophylactic treatment. During the 12-week implementation phase, the pathway was completed on all intubated patients daily., Results: The 12-week trial included a total of 606 days of mechanical ventilation. Checklists were completed for 531 days, a compliance rate of 88% for use of the clinical pathway. Of the 56 patients who were extubated during the trial, 54 had a checklist completed, for 96% compliance on the day of extubation. Outcomes after all nonpalliative extubations (n = 43) during the 12 weeks before and after implementation of the pathway (n = 56 periods) were evaluated by using χ 2 tests. Implementation of the pathway was associated with a significant reduction in rates of postextubation stridor ( χ 2 = 6.2; P = .01), reintubation ( χ 2 = 5.5; P = .02), and reintubation due to postextubation stridor ( χ 2 = 8.3; P = .004)., Conclusion: The clinical pathway implemented in the neurocritical care unit was safe and effective in reducing rates of reintubation and reintubation due to postextubation stridor., (©2018 American Association of Critical-Care Nurses.)

Background: In the acute resuscitation period after traumatic brain injury (TBI), one of the goals is to identify those at risk for secondary neurological decline (ND), represented by a constellation of clinical signs that can be identified as objective events related to secondary brain injury and independently impact outcome. We investigated whether continuous vital sign variability and waveform analysis of the electrocardiogram (ECG) or photoplethysmogram (PPG) within the first hour of resuscitation may enhance the ability to predict ND in the initial 48 hours after traumatic brain injury (TBI). Methods: Retrospective analysis of ND in TBI patients enrolled in the prospective Oximetry and Noninvasive Predictors Of Intervention Need after Trauma (ONPOINT) study. ND was defined as any of the following occurring in the first 48 h: new asymmetric pupillary dilatation (>2 mm), 2 point GCS decline, interval worsening of CT scan as assessed by the Marshall score, or intervention for cerebral edema. Beat-to-beat variation of ECG or PPG, as well as waveform features during the first 15 and 60 min after arrival in the TRU were analyzed to determine physiologic parameters associated with future ND. Physiologic and admission clinical variables were combined in multivariable logistic regression models predicting ND and inpatient mortality. Results: There were 33 (17%) patients with ND among 191 patients (mean age 43 years old, GCS 13, ISS 12, 69% men) who met study criteria. ND was associated with ICU admission ( P < 0.001) and inpatient mortality ( P < 0.001). Both ECG (AUROC: 0.84, 95% CI: 0.76,0.93) and PPG (AUROC: 0.87, 95% CI: 0.80, 0.93) analyses during the first 15 min of resuscitation demonstrated a greater ability to predict ND then clinical characteristics alone (AUROC: 0.69, 95% CI: 0.59, 0.8). Age ( P = 0.02), Marshall score ( P = 0.001), penetrating injury ( P = 0.02), and predictive probability for ND by PPG analysis at 15 min ( P = 0.03) were independently associated with inpatient mortality. Conclusions: Analysis of variability and ECG or PPG waveform in the first minutes of resuscitation may represent a non-invasive early marker of future ND.

Objective: To understand nutritional and inflammatory factors contributing to serum glutamine levels and their relationship to hospital-acquired infections (HAIs) after aneurysmal subarachnoid hemorrhage (SAH)., Methods: A prospective observational study of patients with SAH who had measurements of daily caloric intake and C-reactive protein, transthyretin, tumor necrosis factor α receptor 1a (TNFαR1a), glutamine, and nitrogen balance performed within 4 preset time periods during the 14 days after SAH. Factors associated with glutamine levels and HAIs were analyzed with multivariable regression. HAIs were tracked daily for time-to-event analyses. Outcome 3 months after SAH was assessed by the Telephone Interview for Cognitive Status and modified Rankin Scale., Results: There were 77 patients with an average age of 55 ± 15 years. HAIs developed in 18 (23%) on mean SAH day 8 ± 3. In a multivariable linear regression model, negative nitrogen balance ( p = 0.02) and elevated TNFαR1a ( p = 0.04) were independently associated with higher glutamine levels during the study period. The 14-day mean glutamine levels were lower in patients who developed HAI (166 ± 110 vs 236 ± 81 μg/mL, p = 0.004). Poor admission Hunt and Hess grade ( p = 0.04) and lower glutamine levels ( p = 0.02) predicted time to first HAI. Low 14-day mean levels of glutamine were associated with a poor recovery on the Telephone Interview for Cognitive Status score ( p = 0.03) and modified Rankin Scale score ( p = 0.04) at 3 months after injury., Conclusions: Declining glutamine levels in the first 14 days after SAH are influenced by inflammation and associated with an increased risk of HAI., (© 2018 American Academy of Neurology.)

Objective: The authors sought to evaluate whether a sustained systemic inflammatory response was associated with shunt-dependent hydrocephalus following aneurysmal subarachnoid hemorrhage., Methods: A retrospective analysis of 193 consecutive patients with aneurysmal subarachnoid hemorrhage was performed. Management of hydrocephalus followed a stepwise algorithm to determine the need for external CSF drainage and subsequent shunt placement. Systemic inflammatory response syndrome (SIRS) data were collected for all patients during the first 7 days of hospitalization. Patients who met the SIRS criteria every day for the first 7 days of hospitalization were considered as having a sustained SIRS. Univariate and multivariate regression analyses were used to determine predictors of shunt dependence., Results: Sixteen percent of patients required shunt placement. Sustained SIRS was observed in 35% of shunt-dependent patients compared to 14% in non-shunt-dependent patients (p = 0.004). On multivariate logistic regression, female sex (OR 0.35, 95% CI 0.142-0.885), moderate to severe vasospasm (OR 3.78, 95% CI 1.333-10.745), acute hydrocephalus (OR 21.39, 95% CI 2.260-202.417), and sustained SIRS (OR 2.94, 95% CI 1.125-7.689) were significantly associated with shunt dependence after aneurysmal subarachnoid hemorrhage. Receiver operating characteristic analysis revealed an area under the curve of 0.83 for the final regression model., Conclusions: Sustained SIRS was a predictor of shunt-dependent hydrocephalus following aneurysmal subarachnoid hemorrhage even after adjustment for potential confounding variables in a multivariate logistic regression model.

Importance: Mild traumatic brain injury (mTBI) affects millions of Americans each year. Lack of consistent clinical practice raises concern that many patients with mTBI may not receive adequate follow-up care., Objective: To characterize the provision of follow-up care to patients with mTBI during the first 3 months after injury., Design, Setting, and Participants: This cohort study used data on patients with mTBI enrolled in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study between February 26, 2014, and August 25, 2016. We examined site-specific variations in follow-up care, the types of clinicians seen by patients receiving follow-up care, and patient and injury characteristics associated with a higher likelihood of receiving follow-up care. The TRACK-TBI study is a prospective, multicenter, longitudinal observational study of patients with TBI presenting to the emergency department of 1 of 11 level I US trauma centers. Study data included patients with head trauma who underwent a computed tomography (CT) scan within 24 hours of injury, had a Glasgow Coma Scale score of 13 to 15, were aged 17 years or older, and completed follow-up care surveys at 2 weeks and 3 months after injury (N = 831)., Main Outcomes and Measures: Follow-up care was defined as hospitals providing TBI educational material at discharge, hospitals calling patients to follow up, and patients seeing a physician or other medical practitioner within 3 months after the injury. Unfavorable outcomes were assessed with the Rivermead Post Concussion Symptoms Questionnaire., Results: Of 831 patients (289 [35%] female; 483 [58%] non-Hispanic white; mean [SD] age, 40.3 [16.9] years), less than half self-reported receiving TBI educational material at discharge (353 patients [42%]) or seeing a physician or other health care practitioner within 3 months after injury (367 patients [44%]). Follow-up care varied by study site; adjusting for patient characteristics, the provision of educational material varied from 19% to 72% across sites. Of 236 patients with a positive finding on a CT scan, 92 (39%) had not seen a medical practitioner 3 months after the injury. Adjusting for injury severity and demographics, patient admission to the hospital ward or intensive care unit, patient income, and insurance status were not associated with the probability of seeing a medical practitioner. Among the patients with 3 or more moderate to severe postconcussive symptoms, only 145 of 279 (52%) reported having seen a medical practitioner by 3 months., Conclusions and Relevance: There are gaps in follow-up care for patients with mTBI after hospital discharge, even those with a positive finding on CT or who continue to experience postconcussive symptoms.

Background: Shivering is common during targeted temperature management, and control of shivering can be challenging if clinicians are not familiar with the available options and recommended approaches., Purpose: The purpose of this review was to summarize the most relevant literature regarding various treatments available for control of shivering and suggest a recommended approach based on latest data., Methods: The electronic databases PubMed/MEDLINE and Google Scholar were used to identify studies for the literature review using the following keywords alone or in combination: "shivering treatment," "therapeutic hypothermia," "core temperature modulation devices," and "targeted temperature management.", Results: Nonpharmacologic methods were found to have a very low adverse effect profile and ease of use but some limitations in complete control of shivering. Pharmacologic methods can effectively control shivering, but some have adverse effects, such that risks and benefits to the patient have to be balanced., Conclusion: An approach is provided which suggests that treatment for shivering control in targeted temperature management should be initiated before the onset of therapeutic hypothermia or prior to any attempt at lowering patient core temperature, with medications including acetaminophen, buspirone, and magnesium sulfate, ideally with the addition of skin counterwarming. After that, shivering intervention should be determined with the help of a shivering scale, and stepwise escalation can be implemented that balances shivering treatment with sedation, aiming to provide the most shivering reduction with the least sedating medications and reserving paralytics for the last line of treatment.

Achieving and maintaining normothermia (NT) after subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH) often require temperature modulating devices (TMD). Shivering is a common adverse effect of TMDs that can lead to further costs and complications. We evaluated an esophageal TMD, the EnsoETM (Attune Medical, Chicago, IL), to compare NT performance, shiver burden, and cost of shivering interventions with existing TMDs. Patients with SAH or ICH and refractory fever were treated with the EnsoETM. Patient demographics, temperature data, shiver severity, and amounts and costs of medications used for shiver management were prospectively collected. Controls who received other TMDs were matched for age, gender, and body surface area to EnsoETM recipients, and similar retrospective data were collected. All patients were mechanically ventilated. Fever burden was calculated as areas of curves of time spent above 37.5°C or 38°C. Demographics, temperature data, and costs of EnsoETM recipients were compared with recipients of other TMDs. Eight EnsoETM recipients and 24 controls between October 2015 and November 2016 were analyzed. There were no differences between the two groups in demographics or patient characteristics. No difference was found in temperature at initiation (38.7°C vs. 38.5°C, p = 0.4) and fever burden above 38°C (-0.44°C × hours vs. -0.53°C × hours, p = 0.47). EnsoETM recipients showed a nonsignificant trend in taking longer to achieve NT than other TMDs (5.4 hours vs. 2.9 hours, p = 0.07). EnsoETM recipients required fewer shiver interventions than controls (14 vs. 30, p = 0.02). EnsoETM recipients incurred fewer daily costs than controls ($124.27 vs. $232.76, p = 0.001). The EnsoETM achieved and maintained NT in SAH and ICH patients and was associated with less shivering and lower pharmaceutical costs than other TMDs. Further studies in larger populations are needed to determine the EnsoETM's efficacy in comparison to other TMDs.

Trypanosomes are protistan parasites that diverged early in evolution from most eukaryotes. Their streamlined genomes are packed with arrays of tandemly linked genes that are transcribed polycistronically by RNA polymerase (pol) II. Individual mRNAs are processed from pre-mRNA by spliced leader (SL) trans splicing and polyadenylation. While there is no strong evidence that general transcription factors are needed for transcription initiation at these gene arrays, a RNA pol II transcription pre-initiation complex (PIC) is formed on promoters of SLRNA genes, which encode the small nuclear SL RNA, the SL donor in trans splicing. The factors that form the PIC are extremely divergent orthologues of the small nuclear RNA-activating complex, TBP, TFIIA, TFIIB, TFIIH, TFIIE and Mediator. Here, we functionally characterized a heterodimeric complex of unannotated, nuclear proteins that interacts with RNA pol II and is essential for PIC formation, SL RNA synthesis in vivo, SLRNA transcription in vitro, and parasite viability. These functional attributes suggest that the factor represents TFIIF although the amino acid sequences are too divergent to firmly make this conclusion. This work strongly indicates that early-diverged trypanosomes have orthologues of each and every general transcription factor, requiring them for the synthesis of SL RNA.

Lacosamide is a new-generation antiepileptic drug (AED) that is eliminated by both hepatic and renal mechanisms. Lacosamide elimination by continuous renal replacement therapy (CRRT) has never been studied. The objective of this case report was to describe lacosamide pharmacokinetics in the setting of CRRT. We describe a single patient admitted to the study center with status epilepticus and multiorgan failure. The patient required both continuous venovenous hemofiltration (CVVH) and several AEDs. He was receiving intravenous lacosamide 200 mg twice/day at steady state prior to sampling. Plasma lacosamide concentrations were derived using a validated high-performance liquid chromatography method. Parameters were calculated using Phoenix WinNonlin 7.1 software. The peak concentration at steady state was 7.7 mg/L, the trough concentration was 5.9 mg/L (goal 5-12 mg/L). The volume of distribution was 0.7 L/kg, the elimination half-life was 21 hours, and the sieving coefficient was 0.8 (± 0.06). Lacosamide was cleared by CVVH as demonstrated by the sieving coefficient, but plasma concentrations remained within goal range throughout the dosing interval. These results may suggest that lacosamide 200 mg twice/day is a useful dosing strategy for critically ill patients who require CVVH., (© 2017 Pharmacotherapy Publications, Inc.)

Different mechanisms explain thermoregulatory dysfunction following ischemic stroke, hemorrhagic stroke, and traumatic brain injury. Temperature instability following brain injury likely involves hypothalamic injury, pathologic changes in cerebral blood flow, metabolic derangement, and a neurogenic inflammatory response. Although targeted temperature management (TTM) exerts pleiotropic effects, the heterogeneity of brain injury has hindered identification of patient subsets most likely to benefit from TTM. Early optimism about TTM's role in brain injury has been tempered by the failure of successive clinical trials to show improved patient outcomes. However, given the deleterious effects of fever, aggressive fever management is still warranted in the critically ill neurologic patient., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The potential clinical utility of a novel quantitative electroencephalographic (EEG)-based Brain Function Index (BFI) as a measure of the presence and severity of functional brain injury was studied as part of an independent prospective validation trial. The BFI was derived using quantitative EEG (QEEG) features associated with functional brain impairment reflecting current consensus on the physiology of concussive injury. Seven hundred and twenty adult patients (18-85 years of age) evaluated within 72 h of sustaining a closed head injury were enrolled at 11 U.S. emergency departments (EDs). Glasgow Coma Scale (GCS) score was 15 in 97%. Standard clinical evaluations were conducted and 5 to 10 min of EEG acquired from frontal locations. Clinical utility of the BFI was assessed for raw scores and percentile values. A multinomial logistic regression analysis demonstrated that the odds ratios (computed against controls) of the mild and moderate functionally impaired groups were significantly different from the odds ratio of the computed tomography (CT) postive (CT+, structural injury visible on CT) group (p = 0.0009 and p = 0.0026, respectively). However, no significant differences were observed between the odds ratios of the mild and moderately functionally impaired groups. Analysis of variance (ANOVA) demonstrated significant differences in BFI among normal (16.8%), mild TBI (mTBI)/concussed with mild or moderate functional impairment, (61.3%), and CT+ (21.9%) patients (p < 0.0001). Regression slopes of the odds ratios for likelihood of group membership suggest a relationship between the BFI and severity of impairment. Findings support the BFI as a quantitative marker of brain function impairment, which scaled with severity of functional impairment in mTBI patients. When integrated into the clinical assessment, the BFI has the potential to aid in early diagnosis and thereby potential to impact the sequelae of TBI by providing an objective marker that is available at the point of care, hand-held, non-invasive, and rapid to obtain.

Background: Targeted temperature management (TTM) is often used in neurocritical care to minimize secondary neurologic injury and improve outcomes. TTM encompasses therapeutic hypothermia, controlled normothermia, and treatment of fever. TTM is best supported by evidence from neonatal hypoxic-ischemic encephalopathy and out-of-hospital cardiac arrest, although it has also been explored in ischemic stroke, traumatic brain injury, and intracranial hemorrhage patients. Critical care clinicians using TTM must select appropriate cooling techniques, provide a reasonable rate of cooling, manage shivering, and ensure adequate patient monitoring among other challenges., Methods: The Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacotherapy to form a writing Committee in 2015. The group generated a set of 16 clinical questions relevant to TTM using the PICO format. With the assistance of a research librarian, the Committee undertook a comprehensive literature search with no back date through November 2016 with additional references up to March 2017., Results: The Committee utilized GRADE methodology to adjudicate the quality of evidence as high, moderate, low, or very low based on their confidence that the estimate of effect approximated the true effect. They generated recommendations regarding the implementation of TTM based on this systematic review only after considering the quality of evidence, relative risks and benefits, patient values and preferences, and resource allocation., Conclusion: This guideline is intended for neurocritical care clinicians who have chosen to use TTM in patient care; it is not meant to provide guidance regarding the clinical indications for TTM itself. While there are areas of TTM practice where clear evidence guides strong recommendations, many of the recommendations are conditional, and must be contextualized to individual patient and system needs.

Controlling patient temperature is important for a wide variety of clinical conditions. Cooling to normal or below normal body temperature is often performed for neuroprotection after ischemic insult (e.g. hemorrhagic stroke, subarachnoid hemorrhage, cardiac arrest, or other hypoxic injury). Cooling from febrile states treats fever and reduces the negative effects of hyperthermia on injured neurons. Patients are warmed in the operating room to prevent inadvertent perioperative hypothermia, which is known to cause increased blood loss, wound infections, and myocardial injury, while also prolonging recovery time. There are many reported approaches for temperature management, including improvised methods that repurpose standard supplies (e.g., ice, chilled saline, fans, blankets) but more sophisticated technologies designed for temperature management are typically more successful in delivering an optimized protocol. Over the last decade, advanced technologies have developed around two heat transfer methods: surface devices (water blankets, forced-air warmers) or intravascular devices (sterile catheters requiring vascular placement). Recently, a novel device became available that is placed in the esophagus, analogous to a standard orogastric tube, that provides efficient heat transfer through the patient's core. The device connects to existing heat exchange units to allow automatic patient temperature management via a servo mechanism, using patient temperature from standard temperature sensors (rectal, Foley, or other core temperature sensors) as the input variable. This approach eliminates vascular placement complications (deep venous thrombosis, central line associated bloodstream infection), reduces obstruction to patient access, and causes less shivering when compared to surface approaches. Published data have also shown a high degree of accuracy and maintenance of target temperature using the esophageal approach to temperature management. Therefore, the purpose of this method is to provide a low-risk alternative method for controlling patient temperature in critical care settings.

Introduction: We sought to determine whether compliance with scheduled nimodipine in subarachnoid hemorrhage patients impacted patient outcomes, with the intent of guiding future nimodipine management in patients who experience nimodipine-induced hypotension., Methods: We performed a retrospective analysis of 118 consecutive aneurysmal subarachnoid hemorrhage patients treated with the Maryland Low-Dose IV Heparin Infusion Protocol. Patients were categorized into three independent nimodipine compliance groups: ≥1 dose held, ≥1 dose split, and no missed or split-doses. A split-dose was defined as 30 mg of nimodipine administered every 2 h. Our primary outcome was discharge to home. Bivariate and multivariable logistic regression analyses were used to assess predictors of discharge disposition as a function of nimodipine compliance., Results: Of the 118 patients, 20 (17%) received all nimodipine doses, 6 (5%) received split-doses but never had a full dose held, and 92 (78%) had ≥1 dose held. Forty-five percent of patients were discharged to home, including 75% who received all doses, 67% who received ≥1 split-doses, and 37% with ≥1 missed doses ( p  = 0.003). Multivariable analysis showed that, along with age and World Federation of Neurosurgical Societies grade, nimodipine compliance was an independent predictor of clinical outcome; compared to missing one or more nimodipine doses, full dosing compliance was associated with increased odds of discharge to home (odds ratio 5.20; 95% confidence intervals 1.46-18.56)., Conclusion: In aneurysmal subarachnoid hemorrhage patients with modified Fisher scores 2 through 4 who are cotreated with a low-dose heparin infusion, full compliance with nimodipine dosing was associated with increased odds of discharge to home.

Objectives: A brain electrical activity biomarker for identifying traumatic brain injury (TBI) in emergency department (ED) patients presenting with high Glasgow Coma Scale (GCS) after sustaining a head injury has shown promise for objective, rapid triage. The main objective of this study was to prospectively evaluate the efficacy of an automated classification algorithm to determine the likelihood of being computed tomography (CT) positive, in high-functioning TBI patients in the acute state., Methods: Adult patients admitted to the ED for evaluation within 72 hours of sustaining a closed head injury with GCS 12 to 15 were candidates for study. A total of 720 patients (18-85 years) meeting inclusion/exclusion criteria were enrolled in this observational, prospective validation trial, at 11 U.S. EDs. GCS was 15 in 97%, with the first and third quartiles being 15 (interquartile range = 0) in the study population at the time of the evaluation. Standard clinical evaluations were conducted and 5 to 10 minutes of electroencephalogram (EEG) was acquired from frontal and frontal-temporal scalp locations. Using an a priori derived EEG-based classification algorithm developed on an independent population and applied to this validation population prospectively, the likelihood of each subject being CT+ was determined, and performance metrics were computed relative to adjudicated CT findings., Results: Sensitivity of the binary classifier (likely CT+ or CT-) was 92.3% (95% confidence interval [CI] = 87.8%-95.5%) for detection of any intracranial injury visible on CT (CT+), with specificity of 51.6% (95% CI = 48.1%-55.1%) and negative predictive value (NPV) of 96.0% (95% CI = 93.2%-97.9%). Using ternary classification (likely CT+, equivocal, likely CT-) demonstrated enhanced sensitivity to traumatic hematomas (≥1 mL of blood), 98.6% (95% CI = 92.6%-100.0%), and NPV of 98.2% (95% CI = 95.5%-99.5%)., Conclusion: Using an EEG-based biomarker high accuracy of predicting the likelihood of being CT+ was obtained, with high NPV and sensitivity to any traumatic bleeding and to hematomas. Specificity was significantly higher than standard CT decision rules. The short time to acquire results and the ease of use in the ED environment suggests that EEG-based classifier algorithms have potential to impact triage and clinical management of head-injured patients., (© 2017 by the Society for Academic Emergency Medicine.)

The application of targeted temperature management has become common practice in the neurocritical care setting. It is important to recognize the pathophysiologic mechanisms by which temperature control impacts acute neurologic injury, as well as the clinical limitations to its application. Nonetheless, when utilizing temperature modulation, an organized approach is required in order to avoid complications and minimize side-effects. The most common clinically relevant complications are related to the impact of cooling on hemodynamics and electrolytes. In both instances, the rate of complications is often related to the depth and rate of cooling or rewarming. Shivering is the most common side-effect of hypothermia and is best managed by adequate monitoring and stepwise administration of medications specifically targeting the shivering response. Due to the impact cooling can have upon pharmacokinetics of commonly used sedatives and analgesics, there can be significant delays in the return of the neurologic examination. As a result, early prognostication posthypothermia should be avoided., (© 2017 Elsevier B.V. All rights reserved.)

Objective: Initial hemorrhage burden is an independent predictor for delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the association between clot clearance and DCI still remains to be elucidated., Methods: Quantitative analysis of hemorrhage volume and clot clearance was made in 116 consecutive patients who were scanned within 24 h from onset. Cisternal plus intraventricular hemorrhage volume (CIHV) was calculated as clot volume from the initial scans and scans performed up to 7 days after onset. Clot clearance was calculated as a percentage of residual clot volume compared with the clot volume on the initial scan. Initial clot volume and clot clearance were dichotomized to evaluate the association with DCI., Results: Included patients were aged 55.5±15.2 years with a female preponderance (65.5%, (76/116)). The group with higher initial clot volume (≥17.2 mL) had higher odds for DCI (OR 4.3, 95% CI 1.3 to 14.0, p=0.015). However, the rate of DCI was not different between high and low clot clearance groups (26.7% vs 31.0%, p=0.66). Clot clearance rate was similar in patients with and without DCI up to day 7 after onset., Conclusions: The quantitative clot clearance rate is not an independent predictor for DCI., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Opinion Statement: New neuroprotective treatments aimed at preventing or minimizing "delayed brain injury" are attractive areas of investigation and hold the potential to have substantial beneficial effects on aneurysmal subarachnoid hemorrhage (aSAH) survivors. The underlying mechanisms for this "delayed brain injury" are multi-factorial and not fully understood. The most ideal treatment strategies would have the potential for a pleotropic effect positively modulating multiple implicated pathophysiological mechanisms at once. My personal management (RFJ) of patients with aneurysmal subarachnoid hemorrhage closely follows those treatment recommendations contained in modern published guidelines. However, over the last 5 years, I have also utilized a novel treatment strategy, originally developed at the University of Maryland, which consists of a 14-day continuous low-dose intravenous heparin infusion (LDIVH) beginning 12 h after securing the ruptured aneurysm. In addition to its well-known anti-coagulant properties, unfractionated heparin has potent anti-inflammatory effects and through multiple mechanisms may favorably modulate the neurotoxic and neuroinflammatory processes prominent in aneurysmal subarachnoid hemorrhage. In my personal series of patients treated with LDIVH, I have found significant preservation of neurocognitive function as measured by the Montreal Cognitive Assessment (MoCA) compared to a control cohort of my patients treated without LDIVH (RFJ unpublished data presented at the 2015 AHA/ASA International Stroke Conference symposium on neuroinflammation in aSAH and in abstract format at the 2015 AANS/CNS Joint Cerebrovascular Section Annual Meeting). It is important for academic physicians involved in the management of these complex patients to continue to explore new treatment options that may be protective against the potentially devastating "delayed brain injury" following cerebral aneurysm rupture. Several of the treatment options included in this review show promise and could be carefully adopted as the level of evidence for each improves. Other proposed neuroprotective treatments like statins and magnesium sulfate were previously thought to be very promising and to varying degrees were adopted at numerous institutions based on somewhat limited human evidence. Recent clinical trials and meta-analysis have shown no benefit for these treatments, and I currently no longer utilize either treatment as prophylaxis in my practice.

Objective: Intraventricular nicardipine (IVTN) is a treatment option for severe vasospasm in patients with subarachnoid hemorrhage (SAH). However, its acute effects on cerebral hemodynamics have not been studied in detail., Methods: Between June 2008 and December 2010, IVTN was administered (mainly 4mg every 8h) to 11 SAH patients (54 doses) with multimodality monitoring for refractory vasospasm. Retrospective analyses on physiological parameters were made from baseline and up to 6h after IVTN injection. Statistical analysis was performed with a mixed-effects model., Results: Mean intracranial pressure (ICP) increased slightly, reaching its peak at 20min after IVTN injection (2.5±0.9mmHg (mean±standard error), P<0.01), and decreased gradually thereafter over the next hour. Mean cerebral perfusion pressure transiently decreased 20-30min after injection (3.7±1.8mmHg, P<0.05). Mean arterial pressure, partial pressure of brain oxygen tension (PbtO2), cerebral blood flow (CBF), autoregulation indices did not change significantly. Lactate/pyruvate ratio and glucose remained stable. One patient underwent transcranial Doppler ultrasonography monitoring while on IVTN, which showed a transient increase in mean flow velocity with concomitant decrease in Pulsatility index, suggesting vasodilation in the distal resistance vessels., Conclusions: The vasodilatory effect of IVTN transiently increased ICP, but did not significantly affect PbtO2, CBF or oxidative glucose metabolism in the immediate phase after injection., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In eukaryotes, cyclin-dependent kinases (CDKs) control the cell cycle and critical steps in gene expression. The lethal parasite Trypanosoma brucei, member of the phylogenetic order Kinetoplastida, possesses eleven CDKs which, due to high sequence divergence, were generically termed CDC2-related kinases (CRKs). While several CRKs have been implied in the cell cycle, CRK9 was the first trypanosome CDK shown to control the unusual mode of gene expression found in kinetoplastids. In these organisms, protein-coding genes are arranged in tandem arrays which are transcribed polycistronically. Individual mRNAs are processed from precursor RNA by spliced leader (SL) trans splicing and polyadenylation. CRK9 ablation was lethal in cultured trypanosomes, causing a block of trans splicing before the first transesterification step. Additionally, CRK9 silencing led to dephosphorylation of RNA polymerase II and to hypomethylation of the SL cap structure. Here, we tandem affinity-purified CRK9 and, among potential CRK9 substrates and modifying enzymes, discovered an unusual tripartite complex comprising CRK9, a new L-type cyclin (CYC12) and a protein, termed CRK9-associated protein (CRK9AP), that is only conserved among kinetoplastids. Silencing of either CYC12 or CRK9AP reproduced the effects of depleting CRK9, identifying these proteins as functional partners of CRK9 in vivo. While mammalian cyclin L binds to CDK11, the CRK9 complex deviates substantially from that of CDK11, requiring CRK9AP for efficient CRK9 complex formation and autophosphorylation in vitro. Interference with this unusual CDK rescued mice from lethal trypanosome infections, validating CRK9 as a potential chemotherapeutic target.

Background: Anemia adversely affects cerebral oxygenation and metabolism after subarachnoid hemorrhage (SAH) and is also associated with poor outcome. There is limited evidence to support the use of packed red blood cell (PRBC) transfusion to optimize brain homeostasis after SAH. The aim of this study was to investigate the effect of transfusion on cerebral oxygenation and metabolism in patients with SAH., Methods: This was a prospective observational study in a neurological intensive care unit of a university hospital. Nineteen transfusions were studied in 15 consecutive patients with SAH that underwent multimodality monitoring (intracranial pressure, brain tissue oxygen, and cerebral microdialysis). Data were collected at baseline and for 12 h after transfusion. The relationship between hemoglobin (Hb) change and lactate/pyruvate ratio (LPR) orbrain tissue oxygen (PbtO2) was tested using univariate and multivariable analyses., Results: PRBC transfusion was administered on the median post-bleed day 8. The average Hb concentration at baseline was 8.1 g/dL and increased by 2.2 g/dL after transfusion. PbtO2 increased between hours 2 and 4 post-transfusion and this increase was maintained until hour 10. LPR did not change significantly during the 12-h monitoring period. After adjusting for SpO2, cerebral perfusion pressure, and LPR, the change in Hb concentration was independently and positively associated with a change in PbtO2 (adjusted b estimate = 1.39 [95% confidence interval 0.09-2.69]; P = 0.04). No relationship between the change in Hb concentration and LPR was found., Conclusions: PRBC transfusion resulted in PbtO2 improvement without a clear effect on cerebral metabolism prior to SAH.

Introduction: Subarachnoid hemorrhage (SAH) is a devastating form of stroke. Causes and mechanisms of in-hospital death after SAH in the modern era of neurocritical care remain incompletely understood., Methods: We studied 1200 consecutive SAH patients prospectively enrolled in the Columbia University SAH Outcomes Project between July 1996 and January 2009. Analysis was performed to identify predictors of in-hospital mortality., Results: In-hospital mortality was 18% (216/1200): 3% for Hunt-Hess grade 1 or 2, 9% for grade 3, 24% for grade 4, and 71% for grade 5. The most common adjudicated primary causes of death or neurological devastation leading to withdrawal of support were direct effects of the primary hemorrhage (55%), aneurysm rebleeding (17%), and medical complications (15%). Among those who died, brain death was declared in 42%, 50% were do-not-resuscitate at the time of cardiac death (86% of whom had life support actively withdrawn), and 8% died despite full support. Admission predictors of mortality were age, loss of consciousness at ictus, admission Glasgow Coma Scale score, large aneurysm size, Acute Physiology and Chronic Health Evaluation II (APACHE II) physiologic subscore, and Modified Fisher Scale score. Hospital complications that further increased the risk of dying in multivariable analysis included rebleeding, global cerebral edema, hypernatremia, clinical signs of brain stem herniation, hypotension of less than 90 mm Hg treated with pressors, pulmonary edema, myocardial ischemia, and hepatic failure. Delayed cerebral ischemia, defined as deterioration or infarction from vasospasm, did not predict mortality., Conclusion: Strategies directed toward minimizing early brain injury and aneurysm rebleeding, along with prevention and treatment of medical complication, hold the best promise for further reducing mortality after SAH.

Background: It is common for patients who die from subarachnoid hemorrhage to have a focus on comfort measures at the end of life. The potential role of ethnicity in end-of-life decisions after brain injury has not been extensively studied., Methods: Patients with subarachnoid hemorrhage were prospectively followed in an observational database. Demographic information including ethnicity was collected from medical records and self-reported by patients or their family. Significant in-hospital events including do-not-resuscitate orders, comfort measures only orders (CMO; care withheld or withdrawn), and mortality were recorded prospectively., Results: 1255 patients were included in our analysis: 650 (52 %) were White, 387 (31 %) Hispanic, and 218 (17 %) Black. Mortality was similar between the groups. CMO was more commonly observed in Whites (14 %) compared to either Blacks (10 %) or Hispanics (9 %) (p = 0.04). In a multivariate analysis controlling for age and Hunt-Hess grade, Hispanics were less likely to have CMO than Whites (OR, 0.6; 95 %CI, 0.4-0.9; p = 0.02). Of the 229 patients who died, 77 % of Whites had CMO compared to 54 % of Blacks and 49 % of Hispanics (p < 0.01). In a multivariate analysis, Blacks (OR, 0.3; 95 %CI, 0.2-0.7; p < 0.01) and Hispanics (OR, 0.3; 95 %CI, 0.2-0.6; p < 0.01) were less likely to die with CMO orders than Whites., Conclusion: After subarachnoid hemorrhage, Blacks and Hispanics are less likely to die with CMO orders than Whites. Further research to confirm and investigate the causes of these ethnic differences should be performed.

In trypanosomes, mRNAs are processed by spliced leader (SL) trans splicing, in which a capped SL, derived from SL RNA, is spliced onto the 5' end of each mRNA. This process is mediated by the spliceosome, a large and dynamic RNA-protein machinery consisting of small nuclear ribonucleoproteins (snRNPs) and non-snRNP proteins. Due to early evolutionary divergence, the amino acid sequences of trypanosome splicing factors exhibit limited similarity to those of their eukaryotic orthologs making their bioinformatic identification challenging. Most of the ~ 60 protein components that have been characterized thus far are snRNP proteins because, in contrast to individual snRNPs, purification of intact spliceosomes has not been achieved yet. Here, we characterize the non-snRNP PRP19 complex of Trypanosoma brucei. We identified a complex that contained the core subunits PRP19, CDC5, PRL1, and SPF27, as well as PRP17, SKIP and PPIL1. Three of these proteins were newly annotated. The PRP19 complex was associated primarily with the activated spliceosome and, accordingly, SPF27 silencing blocked the first splicing step. Interestingly, SPF27 silencing caused an accumulation of SL RNA with a hypomethylated cap that closely resembled the defect observed previously upon depletion of the cyclin-dependent kinase CRK9, indicating that both proteins may function in spliceosome activation., (© 2014 John Wiley & Sons Ltd.)

Trypanosoma brucei is a vector borne, lethal protistan parasite of humans and livestock in sub-Saharan Africa. Antigenic variation of its cell surface coat enables the parasite to evade adaptive immune responses and to live freely in the blood of its mammalian hosts. The coat consists of ten million copies of variant surface glycoprotein (VSG) that is expressed from a single VSG gene, drawn from a large repertoire and located near the telomere at one of fifteen so-called bloodstream expression sites (BESs). Thus, antigenic variation is achieved by switching to the expression of a different VSG gene. A BES is a tandem array of expression site-associated genes and a terminal VSG gene. It is polycistronically transcribed by a multifunctional RNA polymerase I (RNAPI) from a short promoter that is located 45-60 kb upstream of the VSG gene. The mechanism(s) restricting VSG expression to a single BES are not well understood. There is convincing evidence that epigenetic silencing and transcription attenuation play important roles. Furthermore, recent data indicated that there is regulation at the level of transcription initiation and that, surprisingly, the VSG mRNA appears to have a role in restricting VSG expression to a single gene. Here, we review BES expression regulation and propose a model in which telomere-directed, epigenetic BES silencing is opposed by BES promoter-directed, activated RNAPI transcription., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To determine the association between exposure to hyperoxia and the risk of delayed cerebral ischaemia (DCI) after subarachnoid haemorrhage (SAH)., Methods: We analysed data from a single centre, prospective, observational cohort database. Patient inclusion criteria were age ≥18 years, aneurysmal SAH, endotracheal intubation with mechanical ventilation, and arterial partial pressure of oxygen (PaO2) measurements. Hyperoxia was defined as the highest quartile of an area under the curve of PaO2, until the development of DCI (PaO2≥173 mm Hg). Poor outcome was defined as modified Rankin Scale 4-6 at 3 months after SAH., Results: Of 252 patients, there were no differences in baseline characteristics between the hyperoxia and control group. Ninety-seven (38.5%) patients developed DCI. The hyperoxia group had a higher incidence of DCI (p<0.001) and poor outcome (p=0.087). After adjusting for modified Fisher scale, rebleeding, global cerebral oedema, intracranial pressure crisis, pneumonia and sepsis, hyperoxia was independently associated with DCI (OR, 3.16; 95% CI 1.69 to 5.92; p<0.001). After adjusting for age, Hunt-Hess grade, aneurysm size, Acute Physiology and Chronic Health Evaluation II score, rebleeding, pneumonia and sepsis, hyperoxia was independently associated with poor outcome (OR, 2.30; 95% CI 1.03 to 5.12; p=0.042)., Conclusions: In SAH patients, exposure to hyperoxia was associated with DCI. Our findings suggest that exposure to excess oxygen after SAH may represent a modifiable factor for morbidity and mortality in this population., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)