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Purpose To advance the implementation of consciousness-promoting therapies in patients with acute disorders of consciousness, the availability of potential therapeutic agents in formulations suitable for administration in hospitalized patients in the presence of complex comorbid conditions is paramount. The purpose of this study is to evaluate the long-term stability of extemporaneously prepared preservative-free methylphenidate hydrochloride (HCl) 5 mg/mL intravenous solution for experimental use. Methods A methylphenidate 5 mg/mL solution was prepared under proper aseptic techniques with Methylphenidate Hydrochloride, USP, powder mixed in sterile water for solution. Methylphenidate HCl 5 mg/mL solution was sterilized by filtration technique under USP <797>–compliant conditions. Samples were stored refrigerated (2-8°C) and analyzed at approximately days 1, 30, 60, 90, 180, and 365. At each time point, chemical and physical stability were evaluated by visual inspection, pH measurement, membrane filtration procedure, turbidometric or photometric technique, and high-performance liquid chromatography analysis. Results Over the 1-year study period, the samples retained 96.76% to 102.04% of the initial methylphenidate concentration. There was no significant change in the visual appearance, pH level, or particulate matter during the study period. The sterility of samples was maintained and endotoxin levels were undetectable throughout the 1-year stability period. Conclusion Extemporaneously prepared preservative-free methylphenidate 5 mg/mL intravenous solution was physically and chemically stable at 32, 61, 95, 186, and 365 days when stored in amber glass vials at refrigerated temperatures (2-8°C). [ABSTRACT FROM AUTHOR]

Background and purpose: Patients with prolonged disorders of consciousness (pDoC) have a high mortality rate due to medical complications. Because an accurate prognosis is essential for decision‐making on patients' management, we analysed data from an international multicentre prospective cohort study to evaluate 2‐year mortality rate and bedside predictors of mortality. Methods: We enrolled adult patients in prolonged vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS) after traumatic and nontraumatic brain injury within 3 months postinjury. At enrolment, we collected demographic (age, sex), anamnestic (aetiology, time postinjury), clinical (Coma Recovery Scale–Revised [CRS‐R], Disability Rating Scale, Nociception Coma Scale–Revised), and neurophysiologic (electroencephalogram [EEG], somatosensory evoked and event‐related potentials) data. Patients were followed up to gather data on mortality up to 24 months postinjury. Results: Among 143 traumatic (n = 55) and nontraumatic (n = 88) patients (VS/UWS, n = 68, 19 females; MCS, n = 75, 22 females), 41 (28.7%) died within 24 months postinjury. Mortality rate was higher in VS/UWS (42.6%) than in MCS (16%; p < 0.001). Multivariate regression in VS/UWS showed that significant predictors of mortality were older age and lower CRS‐R total score, whereas in MCS female sex and absence of alpha rhythm on EEG at study entry were significant predictors. Conclusions: This study demonstrated that a feasible multimodal assessment in the postacute phase can help clinicians to identify patients with pDoC at higher risk of mortality within 24 months after brain injury. This evidence can help clinicians and patients' families to navigate the complex clinical decision‐making process and promote an international standardization of prognostic procedures for patients with pDoC. [ABSTRACT FROM AUTHOR]

Background/objective: For patients with disorders of consciousness (DoC) and their families, the search for new therapies has been a source of hope and frustration. Almost all clinical trials in patients with DoC have been limited by small sample sizes, lack of placebo groups, and use of heterogeneous outcome measures. As a result, few therapies have strong evidence to support their use; amantadine is the only therapy recommended by current clinical guidelines, specifically for patients with DoC caused by severe traumatic brain injury. To foster and advance development of consciousness-promoting therapies for patients with DoC, the Curing Coma Campaign convened a Coma Science Work Group to perform a gap analysis.Methods: We consider five classes of therapies: (1) pharmacologic; (2) electromagnetic; (3) mechanical; (4) sensory; and (5) regenerative. For each class of therapy, we summarize the state of the science, identify gaps in knowledge, and suggest future directions for therapy development.Results: Knowledge gaps in all five therapeutic classes can be attributed to the lack of: (1) a unifying conceptual framework for evaluating therapeutic mechanisms of action; (2) large-scale randomized controlled trials; and (3) pharmacodynamic biomarkers that measure subclinical therapeutic effects in early-phase trials. To address these gaps, we propose a precision medicine approach in which clinical trials selectively enroll patients based upon their physiological receptivity to targeted therapies, and therapeutic effects are measured by complementary behavioral, neuroimaging, and electrophysiologic endpoints.Conclusions: This personalized approach can be realized through rigorous clinical trial design and international collaboration, both of which will be essential for advancing the development of new therapies and ultimately improving the lives of patients with DoC. [ABSTRACT FROM AUTHOR]

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

Background: Consciousness in patients with brain injury is traditionally assessed based on semiological evaluation at the bedside. This classification is limited because of low granularity, ill-defined and rigid nomenclatures incompatible with the highly fluctuating nature of consciousness, failure to identify specific brain states like cognitive motor dissociation, and neglect for underlying biological mechanisms. Here, the authors present a pragmatic framework based on consciousness endotypes that combines clinical phenomenology with all essential physiological and biological data, emphasizing recovery trajectories, therapeutic potentials and clinical feasibility.Methods: The Neurocritical Care Society's Curing Coma Campaign identified an international group of experts who convened in a series of online meetings between May and November 2020 to discuss and propose a novel framework for classifying consciousness.Results: The expert group proposes Advanced Classification of Consciousness Endotypes (ACCESS), a tiered multidimensional framework reflecting increasing complexity and an aspiration to consider emerging and future approaches. Tier 1 is based on clinical phenotypes and structural imaging. Tier 2 adds functional measures including EEG, PET and functional MRI, that can be summarized using the Arousal, Volition, Cognition and Mechanisms (AVCM) score (where "Volition" signifies volitional motor responses). Finally, Tier 3 reflects dynamic changes over time with a (theoretically infinite) number of physiologically distinct states to outline consciousness recovery and identify opportunities for therapeutic interventions.Conclusions: Whereas Tiers 1 and 2 propose an approach for low-resource settings and state-of-the-art expertise at leading academic centers, respectively, Tier 3 is a visionary multidimensional consciousness paradigm driven by continuous incorporation of new knowledge while addressing the Curing Coma Campaign's aspirational goals. [ABSTRACT FROM AUTHOR]

To develop and test the feasibility, reliability and validity of the Coma Recovery Scale-Revised For Accelerated Standardized Testing (CRSR-FAST), a short form of the CRS-R for use in the Intensive Care Unit (ICU). Three trained examiners completed 4 study examinations (1 CRS-R and 3 CRSR-FAST assessments) over a maximum period of 48 hours to establish concurrent validity, interrater reliability and test-retest reliability. The full-length CRS-R served as the reference standard and examiners were masked to patient diagnosis and other CRS-R findings (except for test-retest reliability). Test administration order and assignment of raters to testing condition (i.e., reliability or validity) was pseudo-randomized to prevent order effects. Intensive Care Unit at a Level I trauma center. Forty-five consecutively-enrolled patients with traumatic disorders of consciousness receiving care in the ICU. N/A. Duration of CRSR-FAST administration (feasibility); Agreement between CRSR-FAST and full-length CRS-R determination of consciousness (concurrent validity); Agreement between CRSR-FAST scores obtained by the same rater on two consecutive examinations (test-retest reliability); Agreement between CRSR-FAST scores obtained by two different raters on the same day (inter-rater reliability). Forty-five participants (mean [SD] age 44 [20] years, 67% male, 8 [5] days post injury, CRS-R Total Score = 7 [5], CRS-R range = 1-22) completed the study. The sensitivity, specificity, and accuracy of the CRSR-FAST for detecting consciousness were 81%, 89%, and 84%, respectively. Simple kappa for concurrent validity, Mak's rho for test-retest reliability and inter-rater reliability were 0.68, 0.76 and 0.91, respectively (i.e., substantial). CRSR-FAST administration time was 6.5 [3] minutes. Preliminary findings suggest that the CRSR-FAST is a feasible and valid tool for serial assessment of consciousness in the ICU. The CRSR-FAST may improve diagnostic accuracy, facilitate decision-making regarding continuation of life-sustaining therapy, aid disposition planning, and improve acute and post-acute care coordination. None. [ABSTRACT FROM AUTHOR]

To examine whether women with a history of intimate partner violence (IPV) and traumatic brain injury (TBI) have greater exposure to lifetime trauma relative to women with TBI and no IPV history and to determine the effects of lifetime trauma and community violence on psychological outcomes following TBI. Secondary data analysis of prospective cohort study. Clinical TBI programs at academic medical centers and community-based settings. 72 female participants (age M = 50.5 years, SD = 15.4 years) who sustained at least one complicated mild-severe TBI. Not applicable. The Brain Injury Screening Questionnaire (BISQ) assessed lifetime history of TBI, and the BISQ-IPV module characterized head trauma secondary to IPV. Lifetime trauma exposure was examined with self-report questionnaires assessing adverse childhood experiences (ACEs) and exposure to community violence (CV). Psychological functioning was assessed with the Primary Care Post-traumatic Stress Disorder (PTSD) Screen for DSM-5 and the Quality of Life in Neurological Disorders (Neuro-QOL) Anxiety and Depression scales. Women with IPV and TBI (n = 19) experienced more ACEs (t(23.21) = 3.99, p <.001) and greater CV (t(25.18) = 4.58, p <.001) compared to those with TBI and no IPV history (n = 53). Exposure to CV partially mediated (43.8%) the relationship between ACEs and IPV exposure (indirect effect OR = 1.26, 95% CI= 1.24-1.28). ACEs (β = 0.19, 95% CI = 0.01-0.36) and CV (β = 0.06, 95% CI= 0.00-0.12) predicted worse PTSD symptoms following TBI (F(5, 64) = 8.41, p <.001), while IPV alone did not. The results highlight the need to address lifetime trauma in TBI assessment and treatment, which may aid in improving psychological outcomes. CV may be a key factor in the relationship between ACEs and IPV exposure. Addressing CV could potentially reduce the risk of IPV. The authors have no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]