Restoring consciousness with pharmacologic therapy: Mechanisms, targets, and future directions.

Severe brain injury impairs consciousness by disrupting a broad spectrum of neurotransmitter systems. Emerging evidence suggests that pharmacologic modulation of specific neurotransmitter systems, such as dopamine, promotes recovery of consciousness. Clinical guidelines now endorse the use of amantadine in individuals with traumatic disorders of consciousness (DoC) based on level 1 evidence, and multiple neurostimulants are used off-label in clinical practice, including methylphenidate, modafinil, bromocriptine, levodopa, and zolpidem. However, the relative contributions of monoaminergic, glutamatergic, cholinergic, GABAergic, and orexinergic neurotransmitter systems to recovery of consciousness after severe brain injury are unknown, and personalized approaches to targeted therapy have yet to be developed. This review summarizes the state-of-the-science in the neurochemistry and neurobiology of neurotransmitter systems involved in conscious behaviors, followed by a discussion of how pharmacologic therapies may be used to modulate these neurotransmitter systems and promote recovery of consciousness. We consider pharmacologic modulation of consciousness at the synapse, circuit, and network levels, with a focus on the mesocircuit model that has been proposed to explain the consciousness-promoting effects of various monoaminergic, glutamatergic, and paradoxically, GABAergic therapies. Though fundamental questions remain about neurotransmitter mechanisms, target engagement and optimal therapy selection for individual patients, we propose that pharmacologic therapies hold great promise to promote recovery and improve quality of life for patients with severe brain injuries.

Optimal Timing for Resumption of Anticoagulation After Intracranial Hemorrhage in Patients With Mechanical Heart Valves.

BACKGROUND: Anticoagulation in patients with intracranial hemorrhage (ICH) and mechanical heart valves is often held for risk of ICH expansion; however, there exists a competing risk of acute ischemic stroke (AIS). Optimal timing to resume anticoagulation remains uncertain. METHODS AND RESULTS: We retrospectively studied patients with ICH and mechanical heart valves from 2000 to 2018. The primary outcome was a composite end point of symptomatic hematoma expansion or new ICH, AIS, and intracardiac thrombus up to 30 days post-ICH. The exposure was timing of reinitiation of anticoagulation classified as early (resumed up to 7 days after ICH), late (≥7 and up to 30 days after ICH), and never if not resumed or resumed after 30 days post-ICH. We included 184 patients with ICH and mechanical heart valves (65 anticoagulated early, 100 late, 19 not resumed by day 30 post-ICH). Twelve patients had AIS, 16 new ICH, and 6 intracardiac thromboses. The mean time from ICH to anticoagulation was 12.7 days. Composite outcomes occurred in 12 patients resumed early (18.5%), 14 resumed late (14.0%), and 4 never resumed (21.1%). There was no increased hazard of the composite outcome (hazard ratio [HR], 1.1 [95% CI, 0.2-6.0]), AIS, or worsening or new ICH among patients resumed early versus late. There was no difference in the composite among patients never resumed versus resumed. Patients who never resumed anticoagulation had significantly more severe ICH (median Glasgow Coma Scale: 10.6, 13.9, and 13.9 among those who resumed never, early, and late, respectively; P=0.0001), higher in-hospital mortality (56.5%, 0%, and 0%, respectively; P<0.0001), and an elevated 30-day AIS risk (HR, 15.9 [95% CI, 1.9-129.7], P=0.0098). CONCLUSIONS: In this study of patients with ICH and mechanical heart valves, there was no difference in 30-day thrombotic and hemorrhagic brain-related outcomes when anticoagulation was resumed within 7 versus 7 to 30 days after ICH. Withholding anticoagulation >30 days was associated with severe baseline ICH, higher in-hospital case fatality, and elevated AIS risk.

Evaluation of Bivalirudin During Adult Extracorporeal Membrane Oxygenation: A Retrospective Characterization of Dosing, Efficacy and Bleeding.

Objective: Although heparin is the current standard anticoagulant during venoarterial (VA) and venovenous (VV) extracorporeal membrane oxygenation (ECMO), factors including heparin-induced thrombocytopenia, heparin resistance and drug shortages necessitate alternative anticoagulants such as direct thrombin inhibitors. The aim was to characterize dosing, safety, and efficacy of bivalirudin during ECMO support. Methods: This retrospective single-center study included 24 adults on ECMO support who received ≥6 hours of bivalirudin. The primary endpoint was dose to first therapeutic activated partial thromboplastin time (aPTT). Secondary endpoints included evaluating dosing between ECMO modes, incidence of bleeding and thrombotic events, and time in therapeutic range (TTR). Results: The dose at time of first therapeutic aPTT was bivalirudin 0.05 [0.05-0.1] mg/kg/hour. Bivalirudin dosing requirements were lower in VAECMO compared to VV-ECMO patients and were not impacted by continuous venovenous hemofiltration. Time to therapeutic aPTT was 5.5 [2-13] hours for VA-ECMO and 4.5 [2-8.6] hours for VV-ECMO patients. During any mode of ECMO TTR was 58.3% [39.6-73.1]. Thrombotic events occurred in 3 (13%) patients and major bleeding occurred in 12 (50%) patients. Conclusions: Our findings demonstrated variable bivalirudin dosing requirements based on mode of ECMO and dosing modifications may not be required during CVVH. Factors including mode of ECMO, indication for bivalirudin and concomitant antiplatelet therapy may impact hematologic events. Application of this data can assist with developing a bivalirudin ECMO protocol which provides less variability in initial dosing and TTR.

Evaluation of Medication Exposure on Exacerbation of Disease in Patients With Myasthenia Gravis.

Background and Purpose: In patients with myasthenia gravis (MG), worsening of symptoms poses a risk of respiratory failure which can be precipitated by medication use. Although purported, the risks associated with administration of certain medications are not fully elucidated. Thus, clinical decision support involving a best practice alert was executed to caution providers of drug-disease interactions when ordering a potentially harmful medication. We performed an analysis of the alert overrides with subsequent medication exposure to determine the incidence of MG exacerbations. Methods: This retrospective chart-review evaluated adult patients with MG at 2 large academic medical centers via electronic health records between November-2019 and November-2021 who received a medication following override of the clinical decision support tool. The primary outcome was proportion of patient encounters complicated by myasthenic exacerbations after potentially harmful medication administration. Secondary outcomes included changes in motor strength, length of stay, discharge disposition, unplanned level-of-care escalations, and changes to immunosuppressant therapy following medication administration. Results: A total of 70 orders were assessed in 38 patients across 55 encounters. Medications administered during these encounters included macrolides, fluoroquinolones, ß-blockers, calcium channel blockers, and magnesium sulfate. Exacerbation of disease occurred in 7 patient encounters (12.7%) and occurred after intravenous magnesium or intravenous labetalol. In 5/7 events, at least 1 other risk factor associated with a myasthenic exacerbation was present. Conclusions: Of the medications reported to potentially worsen MG, intravenous labetalol and intravenous magnesium were the 2 agents associated with myasthenic exacerbations with a higher incidence in patients harboring additional risk factors.

Intravenous Ganaxolone: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability in Healthy Adults.

Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA ) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20 mg) or 5 minutes (10 or 30 mg), ganaxolone was detected in plasma with a median Tmax of 5 minutes, whereas a 60-minute infusion (10 or 30 mg) or a bolus (6 mg over 5 minutes) followed by infusion (20 mg/h) for 4 hours achieved a median Tmax of approximately 1 and 3 hours, respectively. Cmax was dose and administration-time dependent, ranging from 73.8 ng/mL (10 mg over 5 minutes) to 1240 ng/mL (30 mg over 5 minutes). Bolus doses above 10 mg of ganaxolone markedly influenced the bispectral index score with a rapid decline; smaller changes occurred on the Modified Observer's Assessment of Alertness/Sedation scale and in quantitative electroencephalogram. Most adverse events were of mild severity, with 2 events of moderate severity; none were reported as serious. No effects on systemic hemodynamics or respiratory functions were reported. Overall, ganaxolone was generally well tolerated at the doses studied and demonstrated pharmacokinetic and pharmacodynamic properties suitable to treat SE.

Multidisciplinary Approach to Sedation and Early Mobility of Intubated Critically Ill Neurologic Patients Improves Mobility at Discharge.

Background and Purpose: Over-sedation may confound neurologic assessment in critically ill neurologic patients and prolong duration of mechanical ventilation (MV). Decreased sedative use may facilitate early functional independence when combined with early mobility. The objective of this study was to evaluate the impact of a stepwise, multidisciplinary analgesia-first sedation pathway and early mobility protocol on medication use and mobility in the neuroscience intensive care unit (ICU). Methods: We performed a single-center prospective cohort study with adult patients admitted to a neuroscience ICU between March and June 2016-2018 who required MV for greater than 48 hours. Patients were included from three separate phases of the study: Phase I - historical controls (2016); Phase II - analgesia-first pathway (2017); Phase III - early mobility protocol (2018). Primary outcomes included propofol requirements during MV, total rehabilitation therapy provided, and functional mobility during ICU admission. Results: 156 patients were included in the analysis. Decreasing propofol exposure was observed during Phase I, II, and III (median 2243.7 mg/day vs 2065.6 mg/day vs 1360.8 mg/day, respectively; P = .04 between Phase I and III). Early mobility was provided in 59.7%, 40%, and 81.6% of patients while admitted to the ICU in Phase I, II, and III, respectively (P < .01). An increased proportion of patients in Phase III were walking or ambulating at ICU discharge (26.7%; 8/30) compared to Phase I (7.9%, 3/38, P = .05). Conclusions: An interdisciplinary approach with an analgesia-first sedation pathway with early mobility protocol was associated with less sedative use, increased rehabilitation therapy, and improved functional mobility status at ICU discharge.

Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Hospital Course, Confounders, and Medications.

The convergence of an interdisciplinary team of neurocritical care specialists to organize the Curing Coma Campaign is the first effort of its kind to coordinate national and international research efforts aimed at a deeper understanding of disorders of consciousness (DoC). This process of understanding includes translational research from bench to bedside, descriptions of systems of care delivery, diagnosis, treatment, rehabilitation, and ethical frameworks. The description and measurement of varying confounding factors related to hospital care was thought to be critical in furthering meaningful research in patients with DoC. Interdisciplinary hospital care is inherently varied across geographical areas as well as community and academic medical centers. Access to monitoring technologies, specialist consultation (medical, nursing, pharmacy, respiratory, and rehabilitation), staffing resources, specialty intensive and acute care units, specialty medications and specific surgical, diagnostic and interventional procedures, and imaging is variable, and the impact on patient outcome in terms of DoC is largely unknown. The heterogeneity of causes in DoC is the source of some expected variability in care and treatment of patients, which necessitated the development of a common nomenclature and set of data elements for meaningful measurement across studies. Guideline adherence in hemorrhagic stroke and severe traumatic brain injury may also be variable due to moderate or low levels of evidence for many recommendations. This article outlines the process of the development of common data elements for hospital course, confounders, and medications to streamline definitions and variables to collect for clinical studies of DoC.

Impact of an enteral nutrition holding guideline on daily nutrition goals in patients taking phenytoin.

BACKGROUND: Concomitant administration of enteral nutrition (EN) and phenytoin decreases phenytoin absorption. Concerns over impaired nutrition, however, may prevent EN from being held surrounding phenytoin administration. This study aimed to evaluate whether EN holding guidelines impacted nutrition goal achievement in patients taking phenytoin. METHODS: Adult patients administered enteral phenytoin for acute or chronic seizures while receiving EN during a neurocritical care admission 6 months before and after EN holding guideline implementation were eligible. Patients without phenytoin concentrations or a clinical registered dietitian assessment were excluded. The primary outcome was the percentage of nutrition daily goals attained before and after implementation. Secondary end points included the incidence of hypoglycemia, differences in measured phenytoin concentrations, and rates of therapeutic (10-20 mcg/ml) and high-therapeutic (15-20 mcg/ml) concentration attainment. Concentrations were adjusted for hypoalbuminemia using the Winter-Tozer equation. RESULTS: Fifty-five patients representing 412 patient days and 1110 phenytoin administrations were included with 29 preimplementation and 26 postimplementation patients. Median percent attainment of daily EN goals was consistent preimplementation and postimplementation (86% vs 83%, P = 0.48). No significant change in rates of days with hypoglycemia was observed. Adjusted phenytoin concentrations were similar before and after implementation (14.1 vs 15.2 mcg/ml, P = 0.45), but the preimplementation cohort had a lower proportion of high-therapeutic concentrations (23% vs 36%, P = 0.018). CONCLUSION: Holding EN for phenytoin did not impact attainment of daily nutrition goals and was not associated with increased rates of hypoglycemia. This is the first study to evaluate the effect of EN holding on nutrition goals in patients receiving phenytoin.

Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study.

BACKGROUND: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent. The goal of the study was to determine if different nimodipine formulations and administration techniques were associated with the safety and effectiveness of nimodipine in aSAH. METHODS: This was a retrospective multicenter observational cohort study conducted in 21 hospitals across North America. Patients admitted with aSAH and received nimodipine by FT for ≥3 days were included. Patient demographics, disease severity, nimodipine administration, and study outcomes were collected. Safety end points included the prevalence of diarrhea and nimodipine dose reduction or discontinuation secondary to blood pressure reduction. Predictors of the study outcomes were analyzed using regression modeling. RESULTS: A total of 727 patients were included. Administration of nimodipine liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (Odds ratio [OR] 2.28, 95% confidence interval [CI] 1.41-3.67, p-value = 0.001, OR 2.76, 95% CI 1.37-5.55, p-value = 0.005, for old and new commercially available formulations, respectively). Bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to hypotension (OR 2.82, 95% CI 1.57-5.06, p-value = 0.001). Tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of delayed cerebral ischemia (OR 6.66, 95% CI 3.48-12.74, p-value <0.0001 and OR 3.92, 95% CI 2.05-7.52, p-value <0.0001, respectively). CONCLUSIONS: Our findings suggest that enteral nimodipine formulations and administration techniques might not be equivalent. This could be attributed to excipient differences, inconsistency and inaccuracy in medication administration, and altered nimodipine bioavailability. Further studies are needed.

Medication Profiles at Hospital Discharge Predict Poor Outcomes After Acute Ischemic Stroke.

Objectives: To examine the relationship between medications prescribed during the first 6-months post-stroke and functional outcome. Materials and Methods: A retrospective analysis of ischemic stroke survivors enrolled in an observational stroke recovery study from June-2017 to July-2019 was performed. Survivors with favorable outcomes (modified rankin scale (mRS) score 0-2) were compared to those with unfavorable outcomes (mRS ≥3) 6-months after stroke on the following: discharge medication classes prescribed, achievement of recommended targets for blood pressure control, glycemic control, and LDL ≤70 mg/dL, medication changes, medication interactions, and medication list discrepancies. Results: Unfavorable 6-month outcomes occurred in 36/78 (46.2%) of survivors. Survivors with unfavorable outcomes were more likely to be prescribed a central nervous system-acting agent (97.2% vs 71.4%; P = .0022) and/or an anti-hyperglycemic agent (25.0% vs 9.5%; P = .009) at discharge. After adjustment of baseline covariates, total number of medications prescribed was associated with unfavorable 6-month outcomes (OR 1.13, 95% CI 1.0-1.28). Secondary stroke prevention measures were not achieved in a high proportion of survivors. Medication changes during 6-month follow up were common and survivors with unfavorable outcomes were more likely to have clinically significant drug-drug interactions. Discussion: At 6-months, survivors with unfavorable outcomes were found to be prescribed more medications, particularly central nervous system-acting and anti-hyperglycemic agents. There were also more drug-drug interactions in the medications prescribed compared to those with favorable outcomes. Together, these data suggest the need for enhanced screening of high-risk stroke survivors focused on close monitoring of polypharmacy, drug-drug interactions, and adverse events with pharmacotherapy.

Implementation of a myasthenia gravis drug-disease interaction clinical decision support tool reduces prescribing of high-risk medications.

INTRODUCTION/AIMS: High-risk medication exposure is a modifiable risk factor for myasthenic exacerbation and crisis. We evaluated whether real-time electronic clinical decision support (CDS) was effective in reducing the rate of prescribing potentially high-risk medications to avoid or use with caution in patients with myasthenia gravis. METHODS: An expert panel reviewed the available drug-disease pairings and associated severity levels to activate the alerts for CDS. All unique alerts activated in both inpatient and outpatient contexts were analyzed over a two-year period. Clinical context, alert severity, medication class, and alert action were collected. The primary outcome was alert override rate. Secondary outcomes included the percentage of unique medication exposures avoided and predictors of alert override. RESULTS: During the analysis period, 2817 unique alerts fired, representing 830 distinct patient-medication exposures for 577 unique patients. The overall alert override rate was 85% (80.3% for inpatient alerts and 95.8% for outpatient alerts). Of unique medication-patient exposures, 19% were avoided because of the alert. Assigned alert severity of "contraindicated" were less likely to be overridden (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.32-0.56), as well as alerts activated during evening staffing (OR 0.69, 95% CI 0.55-0.87). DISCUSSION: Implementation of a myasthenia gravis drug-disease interaction alert reduced overall patient exposure to potentially harmful medications by approximately 19%. Future optimization includes enhanced provider and pharmacist education. Further refinement of alert logic criteria to optimize medication risk reduction and reduce alert fatigue is warranted to support clinicians in prescribing and reduce electronic health record time burden.

Efficacy and Safety of Immediate-Release Nifedipine in Critically Ill Patients.

Background: Immediate-release nifedipine (IRN) is a calcium channel blocker with potent vasodilatory and antihypertensive properties. Safety concerns led to a black box warning for increased risk of myocardial infarction, stroke, and arrhythmias. Objective: The aim of this study was to evaluate the safety and efficacy of IRN for acute blood pressure lowering in critically ill patients. Methods: A retrospective, single-center study was performed in critically ill patients who received at least one dose of IRN. The primary endpoint was the change in systolic blood pressure (SBP) measured at baseline and 1 hour after first administration of IRN. Secondary outcomes included clinically significant hypotension, defined as an absolute reduction in SBP ≥ 15% or vasopressor initiation within 1 hour after administration; incidence of arrhythmias, stroke, or myocardial injury; and time to transition off antihypertensive infusions. Results: IRN resulted in a median [interquartile range] SBP change of -10 [-21 to -1] mmHg between baseline 142 mmHg [124-155] and 1 h post-administration 127 mmHg [114-144]; P < .001. Twenty-seven percent of patients experienced clinically significant hypotension, with hypotension observed in 24% and vasopressors initiated in 4% of patients. Sixteen percent of patients experienced new-onset arrhythmia and 18% experienced myocardial injury following IRN during hospitalization. Median time to transition off intravenous (IV) continuous infusion antihypertensives was 8.5 [0-31.5] hours. Conclusion: IRN led to a reduction in SBP which may have been associated with clinically significant hypotension and need for vasopressor support. Further studies with direct comparisons to alternatives are needed to determine the true association of adverse events with IRN.

Safety and Tolerability of 23.4% Hypertonic Saline Administered Over 2 to 5 Minutes for the Treatment of Cerebral Herniation and Intracranial Pressure Elevation.

BACKGROUND: Hyperosmolar therapy is the cornerstone of medical management of sustained elevated intracranial pressure from cerebral edema. Acute intracranial hypertension and herniation is a medical emergency that requires rapid treatment and stabilization to prevent secondary brain injury or death. Intravenous hypertonic sodium chloride (NaCl) 23.4% is an effective treatment modality commonly used in this setting. Because of its high osmolarity, use has historically been limited primarily to central venous line administration as an intermittent infusion due to concerns about thrombophlebitis, injection site pain, and tissue necrosis or injury with extravasation. The objective of this analysis was to prospectively evaluate the safety of administration of 23.4% NaCl as a rapid intravenous push over 2-5 min. METHODS: A prospective analysis of patients admitted between April 2021 and December 2021 who received 23.4% NaCl intravenous push over 2-5 min in a central or peripheral line was performed. Safety end points included incidence of new onset hypotension [defined as systolic blood pressure (SBP) < 90 mm Hg or SBP decrease of at least 20 mm Hg], bradycardia (defined as heart rate < 50 beats per minute), and infusion site reactions documented within 1 h of administration. For secondary safety outcomes, highest and lowest SBP and lowest heart rates documented within 1 h before 23.4% NaCl administration were compared with values collected within 1 h post administration and evaluated by mixed-design analysis of variance test with adjustment for peripheral versus central line administration. RESULTS: We identified 32 patients who received 79 administrations of 23.4% NaCl through a central line or peripheral line during the study period. An SBP decrease of at least 20 mm Hg was observed in 13% of patients, an SBP < 90 mm Hg occurred in 16% of patients, and bradycardia occurred in 3% of patients who received 23.4% NaCl. Injection site pain was reported by one patient without documented thrombophlebitis, cellulitis, or tissue damage. Pain was not reported during two subsequent administrations in the same patient. There was no documented occurrence of soft tissue injury or necrosis in any patient. Compared with baseline vital signs before 23.4% NaCl administration, no difference in vital signs post administration was observed. CONCLUSIONS: Central and peripheral administration of 23.4% NaCl over 2-5 min was well tolerated, and incidence of hypotension, bradycardia, or infusion site-related adverse events was rare.

Volume replacement is associated with a diminished osmolar effect of mannitol in patients with acute brain injury.

INTRODUCTION: Animal experiments recently demonstrated that replacing urinary loses with crystalloid diminishes the therapeutic effect of mannitol by reducing the increase in osmolality. We aimed to investigate whether this effect is similarly seen in in brain-injured patients by studying the association between total body fluid balance (TBB) and the osmolar response to mannitol. METHODS: We performed a retrospective cohort study of adult patients with acute brain injury between 2015 and 2021 who received ≥ 2 doses of mannitol within 8 hours and no intercurrent concentrated saline solution. We analyzed the association between the change in TBB (∆TBB) and change in osmolality (∆Osm) before and after mannitol in a linear model, both as univariate and after adjustment for common confounding factors. RESULTS: Of 6,145 patients who received mannitol, 155 patients met inclusion criteria (mean age 60 ± 17 years, 48% male, 83% white). The mean total mannitol dose was 2 ± 0.5 g/kg and the mean change in plasma osmolality was 7.9 ± 7.1 mOsm/kg. Each 1 L increase in ∆TBB was associated with a change of -1.1 mOsm/L in ∆Osm (95% CI [-2.2, -0.02], p = 0.045). The magnitude of association was similar to that of total mannitol dose and remained consistent in an adjusted model and after excluding outliers. CONCLUSIONS: In patients with acute brain injury, a positive TBB is associated with a diminished mannitol-induced increase in plasma osmolality. Future prospective studies are needed to confirm these findings and their influence on the therapeutic effect of mannitol.

Pharmacologic Therapies to Promote Recovery of Consciousness.

Pharmacologic interventions are commonly used to support rehabilitation efforts of patients with disorders of consciousness (DoC). The 2018 practice guidelines recommend amantadine in adults with traumatic DoC to promote functional recovery, though several other stimulants are used off-label in clinical practice and trials, such as methylphenidate, bromocriptine, levodopa, and zolpidem. Differences in the mechanisms of action, adverse effects, pharmacokinetics, and drug-drug interactions should be considered when selecting the best agent for each individual patient. Overall, pharmacologic stimulants may provide a safe and inexpensive pathway to increased functionality and participation in rehabilitation. This article provides a concise summary of scientific evidence supporting the use of pharmacologic therapies to stimulate recovery of consciousness in patients with DoC.

Dexmedetomidine and Other Analgosedatives Alter Pupil Characteristics in Critically Ill Patients.

In critically ill patients with neurologic disease, pupil examination abnormalities can signify evolving intracranial pathology. Analgesic and sedative medications (analgosedatives) target pupillary pathways, but it remains unknown how analgosedatives alter pupil findings in the clinical care setting. We assessed dexmedetomidine and other analgosedative associations with pupil reactivity and size in a heterogeneous cohort of critically ill patients with acute intracranial pathology. DESIGN: Retrospective cohort study. SETTING: Two neurologic ICUs between 2016 and 2018. PATIENTS: Critically ill adult patients with pupil measurements within 60 minutes of analgosedative administration. Patients with a history of intrinsic retinal pathology, extracranial injury, inaccessible brain imaging, or no Glasgow Coma Scale (GCS) data were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used mixed-effects linear regression accounting for intrapatient correlations and adjusting for sex, age, GCS score, radiographic mass effect, medication confounders, and ambient light. We tested the association between an initiation or increased IV infusion of dexmedetomidine and pupil reactivity (Neurologic Pupil Index [NPi]) and resting pupil size (mm) obtained using NeurOptics NPi-200 (NeurOptics, Irvine, CA) pupillometer. Of our 221 patients with 9,897 pupil observations (median age, 60 [interquartile range, 50-68]; 59% male), 37 patients (166 pupil observations) were exposed to dexmedetomidine. Dexmedetomidine was associated with higher average NPi (ß = 0.18 per 1 unit increase in rank-normalized NPi ± 0.04; p < 0.001) and smaller pupil size (ß = -0.25 ± 0.05; p < 0.001). Exploratory analyses revealed that acetaminophen was associated with higher average NPi (ß = 0.04 ± 0.02; p = 0.02) and that most IV infusion analgosedatives including propofol, fentanyl, and midazolam were associated with smaller pupil size. CONCLUSIONS: Dexmedetomidine is associated with higher pupil reactivity (high NPi) and smaller pupil size in a cohort of critically ill patients with neurologic injury. Familiarity with expected pupil changes following analgosedative administration is important for accurate interpretation of pupil examination findings, facilitating optimal management of patients with acute intracranial pathology.

Prolonged Unconsciousness is Common in COVID-19 and Associated with Hypoxemia.

OBJECTIVE: The purpose of this study was to estimate the time to recovery of command-following and associations between hypoxemia with time to recovery of command-following. METHODS: In this multicenter, retrospective, cohort study during the initial surge of the United States' pandemic (March-July 2020) we estimate the time from intubation to recovery of command-following, using Kaplan Meier cumulative-incidence curves and Cox proportional hazard models. Patients were included if they were admitted to 1 of 3 hospitals because of severe coronavirus disease 2019 (COVID-19), required endotracheal intubation for at least 7 days, and experienced impairment of consciousness (Glasgow Coma Scale motor score <6). RESULTS: Five hundred seventy-one patients of the 795 patients recovered command-following. The median time to recovery of command-following was 30 days (95% confidence interval [CI] = 27-32 days). Median time to recovery of command-following increased by 16 days for patients with at least one episode of an arterial partial pressure of oxygen (PaO2 ) value ≤55 mmHg (p < 0.001), and 25% recovered ≥10 days after cessation of mechanical ventilation. The time to recovery of command-following  was associated with hypoxemia (PaO2 ≤55 mmHg hazard ratio [HR] = 0.56, 95% CI = 0.46-0.68; PaO2 ≤70 HR = 0.88, 95% CI = 0.85-0.91), and each additional day of hypoxemia decreased the likelihood of recovery, accounting for confounders including sedation. These findings were confirmed among patients without any imagining evidence of structural brain injury (n = 199), and in a non-overlapping second surge cohort (N = 427, October 2020 to April 2021). INTERPRETATION: Survivors of severe COVID-19 commonly recover consciousness weeks after cessation of mechanical ventilation. Long recovery periods are associated with more severe hypoxemia. This relationship is not explained by sedation or brain injury identified on clinical imaging and should inform decisions about life-sustaining therapies. ANN NEUROL 2022;91:740-755.

Stability of extemporaneously prepared preservative-free methylphenidate 5 mg/mL intravenous solution.

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).

Disorders of Consciousness Associated With COVID-19: A Prospective Multimodal Study of Recovery and Brain Connectivity.

BACKGROUND AND OBJECTIVES: In patients with severe coronavirus disease 2019 (COVID-19), disorders of consciousness (DoC) have emerged as a serious complication. The prognosis and pathophysiology of COVID-DoC remain unclear, complicating decisions about continuing life-sustaining treatment. We describe the natural history of COVID-DoC and investigate its associated brain connectivity profile. METHODS: In a prospective longitudinal study, we screened consecutive patients with COVID-19 at our institution. We enrolled critically ill adult patients with a DoC unexplained by sedation or structural brain injury and who were planned to undergo a brain MRI. We performed resting-state fMRI and diffusion MRI to evaluate functional and structural connectivity compared to healthy controls and patients with DoC resulting from severe traumatic brain injury (TBI). We assessed the recovery of consciousness (command following) and functional outcomes (Glasgow Outcome Scale Extended [GOSE] and the Disability Rating Scale [DRS]) at hospital discharge and 3 and 6 months after discharge. We also explored whether clinical variables were associated with recovery from COVID-DoC. RESULTS: After screening 1,105 patients with COVID-19, we enrolled 12 with COVID-DoC. The median age was 63.5 years (interquartile range 55-76.3 years). After the exclusion of 1 patient who died shortly after enrollment, all of the remaining 11 patients recovered consciousness 0 to 25 days (median 7 [5-14.5] days) after the cessation of continuous IV sedation. At discharge, all surviving patients remained dependent: median GOSE score 3 (1-3) and median DRS score 23 (16-30). Ultimately, however, except for 2 patients with severe polyneuropathy, all returned home with normal cognition and minimal disability: at 3 months, median GOSE score 3 (3-3) and median DRS score 7 (5-13); at 6 months, median GOSE score 4 (4-5), median DRS score 3 (3-5). Ten patients with COVID-DoC underwent advanced neuroimaging; functional and structural brain connectivity in those with COVID-DoC was diminished compared to healthy controls, and structural connectivity was comparable to that in patients with severe TBI. DISCUSSION: Patients who survived invariably recovered consciousness after COVID-DoC. Although disability was common after hospitalization, functional status improved over the ensuing months. While future research is necessary, these prospective findings inform the prognosis and pathophysiology of COVID-DoC. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier: NCT04476589.

Early Neurologic Recovery, Practice Pattern Variation, and the Risk of Endotracheal Intubation Following Established Status Epilepticus.

OBJECTIVE: To quantify the association between early neurologic recovery, practice pattern variation, and endotracheal intubation during established status epilepticus, we performed a secondary analysis within the cohort of patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT). METHODS: We evaluated factors associated with the endpoint of endotracheal intubation occurring within 120 minutes of ESETT study drug initiation. We defined a blocked, stepwise multivariate regression, examining 4 phases during status epilepticus management: (1) baseline characteristics, (2) acute treatment, (3) 20-minute neurologic recovery, and (4) 60-minute recovery, including seizure cessation and improving responsiveness. RESULTS: Of 478 patients, 117 (24.5%) were intubated within 120 minutes. Among high-enrolling sites, intubation rates ranged from 4% to 32% at pediatric sites and 19% to 39% at adult sites. Baseline characteristics, including seizure precipitant, benzodiazepine dosing, and admission vital signs, provided limited discrimination for predicting intubation (area under the curve [AUC] 0.63). However, treatment at sites with an intubation rate in the highest (vs lowest) quartile strongly predicted endotracheal intubation independently of other treatment variables (adjusted odds ratio [aOR] 8.12, 95% confidence interval [CI] 3.08-21.4, model AUC 0.70). Site-specific variation was the factor most strongly associated with endotracheal intubation after adjustment for 20-minute (aOR 23.4, 95% CI 6.99-78.3, model AUC 0.88) and 60-minute (aOR 14.7, 95% CI 3.20-67.5, model AUC 0.98) neurologic recovery. CONCLUSIONS: Endotracheal intubation after established status epilepticus is strongly associated with site-specific practice pattern variation, independently of baseline characteristics, and early neurologic recovery and should not alone serve as a clinical trial endpoint in established status epilepticus. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01960075.