Pomalidomide Improves Motor Behavioral Deficits and Protects Cerebral Cortex and Striatum Against Neurodegeneration Through a Reduction of Oxidative/Nitrosative Damages and Neuroinflammation After Traumatic Brain Injury.

Neuronal damage resulting from traumatic brain injury (TBI) causes disruption of neuronal projections and neurotransmission that contribute to behavioral deficits. Cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following TBI. ROS often damage DNA, lipids, proteins, and carbohydrates while RNS attack proteins. The products of lipid peroxidation 4-hydroxynonenal (4-HNE) and protein nitration 3-nitrotyrosine (3-NT) are often used as indicators of oxidative and nitrosative damages, respectively. Increasing evidence has shown that striatum is vulnerable to damage from TBI with a disturbed dopamine neurotransmission. TBI results in neurodegeneration, oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy in the striatum and contribute to motor or behavioral deficits. Pomalidomide (Pom) is a Food and Drug Administration (FDA)-approved immunomodulatory drug clinically used in treating multiple myeloma. We previously showed that Pom reduces neuroinflammation and neuronal death induced by TBI in rat cerebral cortex. Here, we further compared the effects of Pom in cortex and striatum focusing on neurodegeneration, oxidative and nitrosative damages, as well as neuroinflammation following TBI. Sprague-Dawley rats subjected to a controlled cortical impact were used as the animal model of TBI. Systemic administration of Pom (0.5 mg/kg, intravenous [i.v.]) at 5 h post-injury alleviated motor behavioral deficits, contusion volume at 24 h after TBI. Pom alleviated TBI-induced neurodegeneration stained by Fluoro-Jade C in both cortex and striatum. Notably, Pom treatment reduces oxidative and nitrosative damages in cortex and striatum and is more efficacious in striatum (93% reduction in 4-HNE-positive and 84% reduction in 3-NT-positive neurons) than in cerebral cortex (42% reduction in 4-HNE-positive and 55% reduction in 3-NT-positive neurons). In addition, Pom attenuated microgliosis, astrogliosis, and elevations of proinflammatory cytokines in cortical and striatal tissue. We conclude that Pom may contribute to improved motor behavioral outcomes after TBI through targeting oxidative/nitrosative damages and neuroinflammation.

Perceived Utility of Intracranial Pressure Monitoring in Traumatic Brain Injury: A Seattle International Brain Injury Consensus Conference Consensus-Based Analysis and Recommendations.

BACKGROUND: Intracranial pressure (ICP) monitoring is widely practiced, but the indications are incompletely developed, and guidelines are poorly followed. OBJECTIVE: To study the monitoring practices of an established expert panel (the clinical working group from the Seattle International Brain Injury Consensus Conference effort) to examine the match between monitoring guidelines and their clinical decision-making and offer guidance for clinicians considering monitor insertion. METHODS: We polled the 42 Seattle International Brain Injury Consensus Conference panel members' ICP monitoring decisions for virtual patients, using matrices of presenting signs (Glasgow Coma Scale [GCS] total or GCS motor, pupillary examination, and computed tomography diagnosis). Monitor insertion decisions were yes, no, or unsure (traffic light approach). We analyzed their responses for weighting of the presenting signs in decision-making using univariate regression. RESULTS: Heatmaps constructed from the choices of 41 panel members revealed wider ICP monitor use than predicted by guidelines. Clinical examination (GCS) was by far the most important characteristic and differed from guidelines in being nonlinear. The modified Marshall computed tomography classification was second and pupils third. We constructed a heatmap and listed the main clinical determinants representing 80% ICP monitor insertion consensus for our recommendations. CONCLUSION: Candidacy for ICP monitoring exceeds published indicators for monitor insertion, suggesting the clinical perception that the value of ICP data is greater than simply detecting and monitoring severe intracranial hypertension. Monitor insertion heatmaps are offered as potential guidance for ICP monitor insertion and to stimulate research into what actually drives monitor insertion in unconstrained, real-world conditions.

Prognostication and Goals of Care Decisions in Severe Traumatic Brain Injury: A Survey of The Seattle International Severe Traumatic Brain Injury Consensus Conference Working Group.

Abstract Best practice guidelines have advanced severe traumatic brain injury (TBI) care; however, there is little that currently informs goals of care decisions and processes despite their importance and frequency. Panelists from the Seattle International severe traumatic Brain Injury Consensus Conference (SIBICC) participated in a survey consisting of 24 questions. Questions queried use of prognostic calculators, variability in and responsibility for goals of care decisions, and acceptability of neurological outcomes, as well as putative means of improving decisions that might limit care. A total of 97.6% of the 42 SIBICC panelists completed the survey. Responses to most questions were highly variable. Overall, panelists reported infrequent use of prognostic calculators, and observed variability in patient prognostication and goals of care decisions. They felt that it would be beneficial for physicians to improve consensus on what constitutes an acceptable neurological outcome as well as what chance of achieving that outcome is acceptable. Panelists felt that the public should help to define what constitutes a good outcome and expressed some support for a "nihilism guard." More than 50% of panelists felt that if it was certain to be permanent, a vegetative state or lower severe disability would justify a withdrawal of care decision, whereas 15% felt that upper severe disability justified such a decision. Whether conceptualizing an ideal or existing prognostic calculator to predict death or an unacceptable outcome, on average a 64-69% chance of a poor outcome was felt to justify treatment withdrawal. These results demonstrate important variability in goals of care decision making and a desire to reduce this variability. Our panel of recognized TBI experts opined on the neurological outcomes and chances of those outcomes that might prompt consideration of care withdrawal; however, imprecision of prognostication and existing prognostication tools is a significant impediment to standardizing the approach to care-limiting decisions.

Inpatient virtual shared medical appointments to improve health literacy, increase patient self-efficacy, and reduce provider burnout in acute cerebrovascular pathology patients and their caregivers: a pilot study.

OBJECTIVE: Admission to the hospital for an acute cerebrovascular condition such as stroke or brain hemorrhage can be a traumatic and disorienting experience for patients and their family members. The COVID-19 pandemic has further intensified this experience in addition to exacerbating clinician and resident burnout. To ameliorate some of these concerns, a team of resident and medical student trainees implemented a virtual shared medical appointment (vSMA) program for inpatients with acute cerebrovascular disorders and their caregivers. The authors hypothesized that an early intervention in the form of a vSMA improves patient and caregiver health literacy and preparedness while simultaneously educating clinical trainees on effective communication skills and reducing clinician burnout. METHODS: Patients and caregivers of admitted patients were identified through a census of neurosurgery, neurocritical care, and neurology electronic medical records. A weekly 60-minute secure virtual session consisted of introductions and a 10-minute standardized presentation on cerebrovascular disease management, followed by participant-guided discussion. Participants completed presession and postsession surveys. Through this small feasibility study data were obtained regarding present challenges, both expected and unforeseen. RESULTS: A total of 170 patients were screened, and 13 patients and 26 caregivers participated in at least 1 vSMA session. A total of 6 different healthcare providers facilitated sessions. The vSMA program received overwhelmingly positive feedback from caregivers. Survey responses demonstrated that 96.4% of caregivers and 75% of patients were satisfied with the session, 96.4% of caregivers and 87.5% of patients would recommend this type of appointment to a friend or family member, and 88.8% of providers reported feeling validated by conducting the session. The participant group had a 20% greater percentage of patients discharged home without home needs compared to the nonparticipant group. The primary obstacles encountered included technological frustrations with the consent process and the sessions themselves. CONCLUSIONS: Implementation of a vSMA program at a tertiary care center during a pandemic was feasible. Themes caregivers expressed on the postsession survey included better understanding of caring for a stroke patient and coping with the unpredictability of a patient's prognosis. The pandemic has precipitated shifts toward telehealth, but this study highlights the importance of avoiding marginalization of elderly and less technologically inclined populations.

Rationale and Methods for Updated Guidelines for the Management of Penetrating Traumatic Brain Injury.

Penetrating traumatic brain injury (pTBI) affects civilian and military populations resulting in significant morbidity, mortality, and healthcare costs. No up-to-date and evidence-based guidelines exist to assist modern medical and surgical management of these complex injuries. A preliminary literature search revealed a need for updated guidelines, supported by the Brain Trauma Foundation. Methodologists experienced in TBI guidelines were recruited to support project development alongside two cochairs and a diverse steering committee. An expert multi-disciplinary workgroup was established and vetted to inform key clinical questions, to perform an evidence review and the development of recommendations relevant to pTBI. The methodological approach for the project was finalized. The development of up-to-date evidence- and consensus-based clinical care guidelines and algorithms for pTBI will provide critical guidance to care providers in the pre-hospital and emergent, medical, and surgical settings.

Reversal of factor Xa inhibitors associated intracranial haemorrhage at a tertiary medical centre.

Prior to the approval of andexanet, there were no FDA-approved reversal agents indicated for the treatment of factor Xa inhibitor (FXaI) associated major bleed. Four-factor prothrombin complex concentrate (4F-PCC) has been widely used off-label for FXaI-associated bleeding. The purpose of this study was to compare the effectiveness and safety of andexanet and 4F-PCC for the reversal of FXaI-associated intracranial haemorrhage. The primary end point is in-hospital mortality; secondary endpoints include haemostatic efficacy and safety. This study is a singlecentre, retrospective chart review, including patients admitted between 1 January 2016 and 15 August 2019, who received 4F-PCC or andexanet for the management of FXaI-associated intracranial haemorrhage. Of the 45 patients included in this study, 23 patients were in the andexanet group and 22 were in the 4F-PCC group. At index admission, mean age was 76 years and the majority of patients (64%) were on apixaban with 33% presented with Glasgow Coma Scale 24 (GCS) score less than 12. At hospital discharge, 47% of patients in the andexanet group had died or discharged to hospice compared with 45% in the 4F-PCC group. No thromboembolic events were observed in either group within 5 days after administration of the reversal agent. The results of this study suggest that haemostasis and mortality at discharge during the index hospitalization appears to be similar between groups. Prospective randomized control trials comparing safety and efficacy of andexanet and 4F-PCC are needed.

Drug Repurposing in the Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is the most common cause of morbidity among trauma patients; however, an effective pharmacological treatment has not yet been approved. Individuals with TBI are at greater risk of developing neurological illnesses such as Alzheimer's disease (AD) and Parkinson's disease (PD). The approval process for treatments can be accelerated by repurposing known drugs to treat the growing number of patients with TBI. This review focuses on the repurposing of N-acetyl cysteine (NAC), a drug currently approved to treat hepatotoxic overdose of acetaminophen. NAC also has antioxidant and anti-inflammatory properties that may be suitable for use in therapeutic treatments for TBI. Minocycline (MINO), a tetracycline antibiotic, has been shown to be effective in combination with NAC in preventing oligodendrocyte damage. (-)-phenserine (PHEN), an anti-acetylcholinesterase agent with additional non-cholinergic neuroprotective/neurotrophic properties initially developed to treat AD, has demonstrated efficacy in treating TBI. Recent literature indicates that NAC, MINO, and PHEN may serve as worthwhile repositioned therapeutics in treating TBI.

Prone Position Ventilation in Neurologically Ill Patients: A Systematic Review and Proposed Protocol.

OBJECTIVES: Prone positioning has been shown to be a beneficial adjunctive supportive measure for patients who develop acute respiratory distress syndrome. Studies have excluded patients with reduced intracranial compliance, whereby patients with concomitant neurologic diagnoses and acute respiratory distress syndrome have no defined treatment algorithm or recommendations for management. In this study, we aim to determine the safety and feasibility of prone positioning in the neurologically ill patients. DESIGN AND SETTING: A systematic review of the literature, performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses 2009 guidelines, yielded 10 articles for analysis. Using consensus from these articles, in combination with review of multi-institutional proning protocols for patients with nonneurologic conditions, a proning protocol for patients with intracranial pathology and concomitant acute respiratory distress syndrome was developed. MEASUREMENTS AND MAIN RESULTS: Among 10 studies included in the final analysis, we found that prone positioning is safe and feasible in the neurologically ill patients with acute respiratory distress syndrome. Increased intracranial pressure and compromised cerebral perfusion pressure may occur with prone positioning. We propose a prone positioning protocol for the neurologically ill patients who require frequent neurologic examinations and intracranial monitoring. CONCLUSIONS: Although elevations in intracranial pressure and reductions in cerebral perfusion pressure do occur during proning, they may not occur to a degree that would warrant exclusion of prone ventilation as a treatment modality for patients with acute respiratory distress syndrome and concomitant neurologic diagnoses. In cases where intracranial pressure, cerebral perfusion pressure, and brain tissue oxygenation can be monitored, prone position ventilation should be considered a safe and viable therapy.

Outcomes and Clinical Characteristics of Intracranial Hemorrhage in Patients with Hematologic Malignancies: A Systematic Literature Review.

BACKGROUND: Many clinical and demographic factors can influence survival of patients with hematologic malignancies who have intracranial hemorrhages (ICHs). Understanding the influence of these factors on patient survival can guide treatment decisions and may inform prognostic discussions. We conducted a systematic literature review to determine survival of patients with intracranial hemorrhages and concomitant hematologic malignancy. METHODS: A systematic literature review was conducted and followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. PubMed/MEDLINE, Web of Science, Ovid, SCOPUS, and Embase databases were queried with the following terms: ("intracranial hemorrhages" OR "brain hemorrhage" OR "cerebral hemorrhage" OR "subdural hematoma" OR "epidural hematoma" OR "intraparenchymal hemorrhage") AND ("Hematologic Neoplasms" OR "Myeloproliferative Disorders" OR "Myelofibrosis" OR "Essential thrombocythemia" OR "Leukemia"). Abstracts and articles were screened according to inclusion and exclusion criteria that were determined a priori. RESULTS: Literature review yielded 975 abstracts from which a total of 68 full-text articles were reviewed. Twelve articles capturing 634 unique patients were included in the final qualitative analysis. Median overall survival for all patients ranged from 20 days to 1.5 months while median overall survival for the subset of patients having ICH within 10 days of diagnosis of hematologic malignancy was 5 days. Intraparenchymal hemorrhages, multiple foci of hemorrhage, transfusion-resistant low platelet counts, leukocytosis, low Glasgow Coma Scale scores at presentation, and ICH early in treatment course were associated with worse outcomes. CONCLUSIONS: Survival for patients with hematologic malignancies and concomitant ICHs remains poor. Early detection, recognition of poor prognostic factors, and correction of hematologic abnormalities essential to prevention and treatment of ICHs in this patient population.

Pharmacologic Treatment of Neurobehavioral Sequelae Following Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of disability in the United States. With decreasing mortality rates, a higher number of patients are impacted by long-term neuropsychiatric sequelae, such as cognitive deficits, depression, anxiety, and sleep-wake disorders. These sequelae are primarily driven by the disruption of key neurotransmitter homeostasis including dopamine, norepinephrine, serotonin, and acetylcholine. Neurostimulants are centrally acting medications used to assist in restoring these neurotransmitter abnormalities and are pharmacologic options to ameliorate symptoms in post-TBI patients. Examples of neurostimulants include amantadine, selective serotonin reuptake inhibitors, tricyclic antidepressants, central stimulants (ie, methylphenidate), modafinil, and donepezil. Large, well-powered studies have not been performed to validate their use in patients with TBI, leaving uncertainty for these agents' place in therapy. Current practice is driven by consideration of patient-specific factors to select the most appropriate agent. This review provides clinicians with a summary of the available literature on neurostimulants following TBI to guide appropriate usage to help improve patients' symptoms and optimize safety.

A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC).

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.

Anesthetic Management of Elderly Patients With Down Syndrome: A Case Report.

In 1930, the life expectancy of patients with Down syndrome was about 10 years; today, their life expectancy is more than 60 years. With aging, there is an increased need for anesthesia and surgery. There is, however, no published information regarding the anesthetic management of older adults with Down syndrome. In this report, we described the anesthetic management of a 50-year-old woman with Down syndrome undergoing major cervical spine surgery. Components of the anesthetic that we thought would be difficult such as intravenous line placement and endotracheal intubation were accomplished without difficulty. Despite our best efforts, our patient nevertheless experienced both emergence delirium and postoperative vomiting. We advocate that physicians, advanced practice providers, and registered nurses be aware of the unique perianesthesia needs of older patients with Down syndrome.

Cerebrospinal Fluid Drainage During Endovascular Aortic Aneurysm Repair: A Systematic Review of the Literature and Treatment Recommendations.

INTRODUCTION: Spinal cord injury (SCI) is a known complication of aortic aneurysm repair. Previous reports indicate that cerebrospinal fluid drainage (CSFD) may reduce incidence of SCI during open aortic aneurysm repair but its utility in endovascular repair remains poorly understood. We performed a systematic review of the literature to examine the protocols and outcomes of CSFD in patients undergoing endovascular aortic aneurysm repair. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were utilized to conduct a systematic literature review. PubMed, Scopus, Ovid, Cochrane, and EMBASE were queried for articles published since 2016 using search terms "(cerebrospinal fluid diversion OR CSF diversion OR lumbar drain OR subarachnoid drain OR spinal) AND (aortic aneurysm AND thoracic AND endovascular OR TEVAR)." Ninety-two articles were identified and screened by 2 independent reviewers, and 23 studies met criteria for full-text review after initial screening. RESULTS: A total of 8 studies met full inclusion criteria for final analysis. Six studies reported incidence of SCI in patients with CSFD and 2 compared SCI incidence between patients with and without CSFD. Protocols for drainage most commonly included draining to a target pressure intra- and postoperatively, between 8 and 12 mm Hg. Incidence of SCI ranged from 0% to 17% in patients with CSFD, and from 0% to 50% in those without CSFD. Rates of CSFD-related complications ranged from <1% to 28%. CONCLUSION: There may be a protective benefit of CSFD in preventing SCI, but there remains significant variation in drain placement protocols. Significant potential bias exists in the reviewed data. Higher quality studies on the role of CSFD in endovascular aortic aneurysm repair are needed.

A management algorithm for patients with intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC).

BACKGROUND: Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based. METHODS: We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations. RESULTS: We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination. CONCLUSIONS: Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.

Outcomes After Intracranial Hemorrhage in Patients with Left Ventricular Assist Devices: A Systematic Review of Literature.

BACKGROUND: Intracranial hemorrhage (ICH) is a common complication in patients with left ventricular assist devices (LVADs) and carries a dismal prognosis. Limited data are available on the management and outcomes in this population, which are essential to determine an optimal treatment strategy. We conducted a systematic literature review to determine the clinical characteristics and survival of this population. METHODS: PubMed, Ovid, Embase. Scopus, Cochrane, CENTRAL, and Web of Science articles were selected using the following terms: ("Heart-Assist Devices" or "left ventricular assist device" or "LVAD") AND ("intracranial hemorrhage" OR "cerebral hemorrhage" OR "brain hemorrhage" OR "intracerebral hemorrhage" OR "intraparenchymal hemorrhage" OR "hemorrhagic stroke"). Abstracts and articles were screened according to inclusion and exclusion criteria that were determined a priori. Potential studies were reviewed by 4 authors, who reached a consensus on the final studies to be included. RESULTS: The literature review yielded 609 abstracts, which were screened according to predetermined inclusion criteria. A total of 143 full-text articles were reviewed, and 8 articles were included in the final qualitative analysis. These studies reviewed data for 597 patients with LVADs who had ICH. The mortality for ICH was widely variable across studies and ranged from 16% to 100%. CONCLUSIONS: There is minimal existing literature on patients with LVAD with ICH that report patient outcomes in a nonstandardized fashion. The studies included in this analysis report mortality consistent with previous reports, indicating a need for further investigation to identify risk factors and improve outcomes in these patients.

Subdural Hematoma in Patients with Hematologic Malignancies: An Outcome Analysis and Examination of Risk Factors of Operative and Nonoperative Management.

BACKGROUND: Patients with hematologic disorders who present with subdural hematomas (SDH) present a surgical decision-making challenge. Because of intrinsic coagulopathy, platelet dysfunction, and immunosuppression, surgical intervention poses a unique set of risks. OBJECTIVE: To describe a clinical sample of patients with hematologic disorders and concurrent SDH, to compare baseline and outcome variables, including complication rates and survival, in surgical versus nonsurgical management, and to identify clinical variables that may predict outcomes. METHODS: A 12-year retrospective case-control study was carried out of 50 adult patients with hematologic malignancies and SDH. Patients underwent surgical evacuation for SDH. Controls did not. Outcomes included discharge disposition, Glasgow Outcome Scale score, 30-day mortality, and overall survival. Complications included seizure, reoperation, and readmission. A Fisher exact test or χ2 analysis compared categorical variables; continuous outcomes were compared with a Student t test. A Kaplan-Meier survival analysis was performed and multivariable Cox logistic regression evaluated variables associated with overall mortality. RESULTS: Surgical and nonsurgical groups differed only by Glasgow Coma Scale score, with slightly lower Glasgow Coma Scale scores in the surgical group. Complication rates did not differ; however, the 30-day reoperation rate was 35% for the surgical cohort. Overall, seizure incidence was 18%, readmission was 30%, 30-day mortality was 38%, median survival was 140.5 days, and 75% had a Glasgow Outcome Scale score of 1-3 at censorship. Increased age, low hemoglobin levels, and low platelet levels were associated with increased risk of mortality. CONCLUSIONS: Low platelet and hemoglobin levels are consistent markers of poor prognosis and surgical intervention, either as a proxy of or as a cause for clinical deterioration, is associated with increased mortality risk.

Complexity Analysis of Decision-Making in the Critically Ill.

RATIONALE: Despite multiple trials of interventions to improve end-of-life care of the critically ill, there is a persistent lack of understanding of factors associated with barriers to decision-making at the end of life. OBJECTIVE: To apply the principles of complexity science in examining the extent to which transitions to end-of-life care can be predicted by physician, family, or patient characteristics; outcome expectations; and the evaluation of treatment effectiveness. METHODS: A descriptive, longitudinal study was conducted in 3 adult intensive care units (ICUs). Two hundred sixty-four family surrogates of patients lacking decisional capacity and the physicians caring for the patients were interviewed every 5 days until ICU discharge or patient death. MEASUREMENTS: Characteristics of patients, physicians, and family members; values and preferences of physicians and family; and evaluation of treatment effectiveness, expectations for patient outcomes, and relative priorities in treatment (comfort vs survival). The primary outcome, focus of care, was categorized as (1) maintaining a survival orientation (no treatment limitations), (2) transitioning to a stronger palliative focus (eg, some treatment limitations), or (3) transitioning to an explicit end-of-life, comfort-oriented care plan. MAIN RESULTS: Physician expectations for survival and future cognitive status were the only variables consistently and significantly related to the focus of care. Neither physician or family evaluations of treatment effectiveness nor what was most important to physicians or family members was influential. CONCLUSION: Lack of influence of family and physician views, in comparison to the consistent effect of survival probabilities, suggests barriers to incorporation of individual values in treatment decisions.

Use of a surgical rehearsal platform and improvement in aneurysm clipping measures: results of a prospective, randomized trial.

OBJECTIVE The field of neurosurgery is constantly undergoing improvements and advances, both in technique and technology. Cerebrovascular neurosurgery is no exception, with endovascular treatments changing the treatment paradigm. Clipping of aneurysms is still necessary, however, and advances are still being made to improve patient outcomes within the microsurgical treatment of aneurysms. Surgical rehearsal platforms are surgical simulators that offer the opportunity to rehearse a procedure prior to entering the operative suite. This study is designed to determine whether use of a surgical rehearsal platform in aneurysm surgery is helpful in decreasing aneurysm dissection time and clip manipulation of the aneurysm. METHODS The authors conducted a blinded, prospective, randomized study comparing key effort and time variables in aneurysm clip ligation surgery with and without preoperative use of the SuRgical Planner (SRP) surgical rehearsal platform. Initially, 40 patients were randomly assigned to either of two groups: one in which surgery was performed after use of the SRP (SRP group) and one in which surgery was performed without use of the SRP (control group). All operations were videotaped. After exclusion of 6 patients from the SRP group and 9 from the control group, a total of 25 surgical cases were analyzed by a reviewer blinded to group assignment. The videos were analyzed for total microsurgical time, number of clips used, and number of clip placement attempts. Means and standard deviations (SDs) were calculated and compared between groups. RESULTS The mean (± SD) amount of operative time per clip used was 920 ± 770 seconds in the SRP group and 1294 ± 678 seconds in the control group (p = 0.05). In addition, the mean values for the number of clip attempts, total operative time, ratio of clip attempts to clips used, and time per clip attempt were all lower in the SRP group, although the between-group differences were not statistically significant. CONCLUSIONS Preoperative rehearsal with SRP increased efficiency and safety in aneurysm microsurgery as demonstrated by the statistically significant improvement in time per clip used. Although the rest of the outcomes did not demonstrate statistically significant between-group differences, the fact that the SRP group showed improvement in mean values for all measures studied suggests that preoperative rehearsal may increase the efficiency and safety of aneurysm microsurgery. Future studies aimed at improving patient outcome and safety during surgical clipping of aneurysms will be needed to keep pace with the quickly advancing endovascular field.

ICES (Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery) for Brain Hemorrhage: A Multicenter Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating disease without a proven therapy to improve long-term outcome. Considerable controversy about the role of surgery remains. Minimally invasive endoscopic surgery for ICH offers the potential of improved neurological outcome. METHODS: We tested the hypothesis that intraoperative computerized tomographic image-guided endoscopic surgery is safe and effectively removes the majority of the hematoma rapidly. A prospective randomized controlled study was performed on 20 subjects (14 surgical and 4 medical) with primary ICH of >20 mL volume within 48 hours of ICH onset. We prospectively used a contemporaneous medical control cohort (n=36) from the MISTIE trial (Minimally Invasive Surgery and r-tPA for ICH Evacuation). We evaluated surgical safety and neurological outcomes at 6 months and 1 year. RESULTS: The intraoperative computerized tomographic image-guided endoscopic surgery procedure resulted in immediate reduction of hemorrhagic volume by 68±21.6% (interquartile range 59-84.5) within 29 hours of hemorrhage onset. Surgery was successfully completed in all cases, with a mean operative time of 1.9 hours (interquartile range 1.5-2.2 hours). One surgically related bleed occurred peri-operatively, but no patient met surgical safety stopping threshold end points for intraoperative hemorrhage, infection, or death. The surgical intervention group had a greater percentage of patients with good neurological outcome (modified Rankin scale score 0-3) at 180 and 365 days as compared with medical control subjects (42.9% versus 23.7%; P=0.19). CONCLUSIONS: Early computerized tomographic image-guided endoscopic surgery is a safe and effective method to remove acute intracerebral hematomas, with a potential to enhance neurological recovery. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00224770.

Mitochondria: A Therapeutic Target for Parkinson's Disease?

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The exact causes of neuronal damage are unknown, but mounting evidence indicates that mitochondrial-mediated pathways contribute to the underlying mechanisms of dopaminergic neuronal cell death both in PD patients and in PD animal models. Mitochondria are organized in a highly dynamic tubular network that is continuously reshaped by opposing processes of fusion and fission. Defects in either fusion or fission, leading to mitochondrial fragmentation, limit mitochondrial motility, decrease energy production and increase oxidative stress, thereby promoting cell dysfunction and death. Thus, the regulation of mitochondrial dynamics processes, such as fusion, fission and mitophagy, represents important mechanisms controlling neuronal cell fate. In this review, we summarize some of the recent evidence supporting that impairment of mitochondrial dynamics, mitophagy and mitochondrial import occurs in cellular and animal PD models and disruption of these processes is a contributing mechanism to cell death in dopaminergic neurons. We also summarize mitochondria-targeting therapeutics in models of PD, proposing that modulation of mitochondrial impairment might be beneficial for drug development toward treatment of PD.