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Background/Objective Neurostimulants may improve or accelerate cognitive and functional recovery after intracerebral hemorrhage (ICH), ischemic stroke (IS), or subarachnoid hemorrhage (SAH), but few studies have described their safety and effectiveness in the intensive care unit (ICU). The objective of this study was to describe amantadine and modafinil administration practices during acute stroke care starting in the ICU and to evaluate safety and effectiveness. Methods Consecutive adult ICU patients treated with amantadine and/or modafinil following acute non-traumatic IS, ICH, or SAH were evaluated. Neurostimulant administration data were extracted from the electronic medication administration record, including medication (amantadine, modafinil, or both), starting dose, time from stroke to initiation, and whether the neurostimulant was continued at hospital discharge. Patients were considered responders if they met two of three criteria within 9 days of neurostimulant initiation: increase in Glasgow coma scale (GCS) score ≥ 3 points from pre-treatment baseline, improved wakefulness or participation documented in caregiver notes, or clinical improvement documented in physical or occupational therapy notes. Potential confounders of the effectiveness assessment and adverse drug effects were also recorded. Results A total of 87 patients were evaluable during the 3.7-year study period, including 41 (47%) with ICH, 29 (33%) with IS, and 17 (20%) with SAH. The initial neurostimulant administered was amantadine in 71 (82%) patients, modafinil in 13 (15%), or both in 3 (3%) patients. Neurostimulants were initiated a median of 7 (4.25, 12.75) days post-stroke (range 1–27 days) for somnolence (77%), not following commands (32%), lack of eye opening (28%), or low GCS (17%). The most common starting dose was 100 mg twice daily for both amantadine (86%) and modafinil (54%). Of the 79 patients included in the effectiveness evaluation, 42 (53%) were considered responders, including 34/62 (55%) receiving amantadine monotherapy and 8/24 (33%) receiving both amantadine and modafinil at the time they met the definition of a responder. No patient receiving modafinil monotherapy was considered a responder. The median time from initiation to response was 3 (2, 5) days. Responders were more frequently discharged home or to acute rehabilitation compared to non-responders (90% vs 62%, p = 0.006). Among survivors, 63/72 (88%) were prescribed a neurostimulant at hospital discharge. The most common potential adverse drug effect was sleep disruption (16%). Conclusions Neurostimulant administration during acute stroke care may improve wakefulness. Future controlled studies with a neurostimulant administration protocol, prospective evaluation, and discretely defined response and safety criteria are needed to confirm these encouraging findings. Electronic supplementary material The online version of this article (10.1007/s12028-020-00986-4) contains supplementary material, which is available to authorized users.

The absence of the pupillary light reflex (PLR) 3 days after cardiac arrest predicts poor outcome, but quantitative PLR assessment with pupillometry early after recovery of spontaneous circulation (ROSC) and throughout targeted temperature management (TTM) has rarely been evaluated. Fifty-five adult patients treated with TTM with available pupillometry data from the NeurOptics NPi-200 were studied. Discharge outcome was classified good if the cerebral performance category score was 1–2, poor if 3–5. Pupil size, PLR percent constriction (%PLR), and constriction velocity (CV) were determined at TTM start and 6 (± 2)-h post-ROSC (“early”), and throughout TTM using data from the worst eye at each assessment. The Neurological Pupil index (NPi) was also determined at each pupil assessment; the NPi is scored from 0 (nonreactive) to 5 (brisk) with values

Importance Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration ClinicalTrials.gov:NCT04332991

Amantadine and modafinil are neurostimulants that may improve cognitive and functional recovery post-stroke, but the existing study results vary, and no comprehensive review has been published. This systematic review describes amantadine and modafinil administration practices post-stroke, evaluates timing and impact on clinical effectiveness measures, and identifies the incidence of potential adverse drug effects. A librarian-assisted search of the MEDLINE (PubMed) and EMBASE databases identified all English-language publications with “amantadine” or “modafinil” in the title or abstract from inception through February 1, 2020. Publications meeting predefined Patient, Intervention, Comparator, Outcome (PICO) criteria were included: Patients (≥ 18 years of age post-stroke); Intervention (amantadine or modafinil administration); Comparison (pretreatment baseline or control group); Outcomes (cognitive or functional outcome). Amantadine and modafinil administration practices, cognitive and functional outcomes, and incidence of potential adverse drug effects were collected following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidance. Quantitative analyses were not performed due to heterogeneity in the clinical effectiveness measures; descriptive data are presented as number (percent) or median (interquartile range). Of 12,620 publications initially identified, 10 amantadine publications (n = 121 patients) and 12 modafinil publications (n = 120 patients) were included. Amantadine was initiated 39 (16, 385) days post-stroke, with most common initial doses of 100 mg once or twice daily (range 100–200 mg/day), and final daily dose of 200 (188, 200) mg/day. Modafinil was initiated 170 (17, 496) days post-stroke, with initial and final daily doses of 100 (100, 350) mg/day and 200 (100, 350) mg/day, respectively. The most common indication was consciousness disorders for amantadine (n = 3/10 publications; 30%) and fatigue for modafinil (n = 5/12; 42%). Forty unique clinical effectiveness measures (1.8 per study) with 141 domains (6.4 per study) were described across all studies. A positive response in at least one clinical effectiveness measure was reported in 70% of amantadine publications and 83% of modafinil publications. Only one publication each for amantadine (10%; n = 5 patients) and modafinil (8%; n = 21 patients) studied acutely hospitalized or ICU patients; both were randomized studies showing improvements in neurocognitive function for amantadine and fatigue for modafinil. Potential adverse drug effects were reported in approximately 50% of publications, most commonly visual hallucinations with amantadine (2% of patients) and dizziness (5% of patients) and dry eyes or mouth (5% of patients). Amantadine and modafinil may improve cognitive and functional recovery post-stroke, but higher-quality data are needed to confirm this conclusion, especially in the acute care setting.

Background Patients resuscitated from cardiac arrest ( CA ) have highly variable neurological, circulatory, and systemic ischemia‐reperfusion injuries. After the initial hypoxic‐ischemic insult, a cascade of immune and inflammatory responses develops and is often fatal. The role of the immune response in pathophysiological characteristics and recovery is not well understood. We studied immune cell activity and its association with outcomes in a cohort of CA survivors. Methods and Results After informed consent, we collected blood samples at intervals over a week after resuscitation from CA . We examined the expression of CD 39 and CD 73 (alias 5′‐nucleotidase), production of tumor necrosis factor‐α, generation of reactive oxygen species, and secretion of vascular endothelial growth factor by circulating myeloid and lymphoid cells, in comparison to cells obtained from control subjects before coronary artery bypass grafting surgery. The number of circulating total and CD 73‐expressing lymphocytes correlated with survival after CA . Incubation of immune cells, obtained from post‐ CA subjects, with AMP , a substrate for CD 73, resulted in inhibition of tumor necrosis factor‐α production and generation of reactive oxygen species. This effect was blocked by adenosine 5′‐(α, β‐methylene) diphosphate, a specific inhibitor of CD 73 and ZM 241385, an A2 adenosine receptor antagonist. We also found that AMP ‐dependent activation of CD 73 induces production of vascular endothelial growth factor. Conclusions CD 73‐expressing lymphocytes mediate cellular protection from inflammation after CA through inhibition of proinflammatory activation of myeloid cells and promotion of vascular endothelial growth factor secretion. The contribution of CD 73 lymphocytes in the regulation of acute inflammation and tissue injury after CA warrants further study.