Showing papers in "Neurocritical Care in 2021"

Neurological Involvement in COVID-19 and Potential Mechanisms: A Review.

Abstract: As the current understanding of COVID-19 continues to evolve, a synthesis of the literature on the neurological impact of this novel virus may help inform clinical management and highlight potentially important avenues of investigation. Additionally, understanding the potential mechanisms of neurologic injury may guide efforts to better detect and ameliorate these complications. In this review, we synthesize a range of clinical observations and initial case series describing potential neurologic manifestations of COVID-19 and place these observations in the context of coronavirus neuro-pathophysiology as it may relate to SARS-CoV-2 infection. Reported nervous system manifestations range from anosmia and ageusia, to cerebral hemorrhage and infarction. While the volume of COVID-19-related case studies continues to grow, previous work examining related viruses suggests potential mechanisms through which the novel coronavirus may impact the CNS and result in neurological complications. Namely, animal studies examining the SARS-CoV have implicated the angiotensin-converting-enzyme-2 receptor as a mediator of coronavirus-related neuronal damage and have shown that SARS-CoV can infect cerebrovascular endothelium and brain parenchyma, the latter predominantly in the medial temporal lobe, resulting in apoptosis and necrosis. Human postmortem brain studies indicate that human coronavirus variants and SARS-CoV can infect neurons and glia, implying SARS-CoV-2 may have similar neurovirulence. Additionally, studies have demonstrated an increase in cytokine serum levels as a result of SARS-CoV infection, consistent with the notion that cytokine overproduction and toxicity may be a relevant potential mechanism of neurologic injury, paralleling a known pathway of pulmonary injury. We also discuss evidence that suggests that SARS-CoV-2 may be a vasculotropic and neurotropic virus. Early reports suggest COVID-19 may be associated with severe neurologic complications, and several plausible mechanisms exist to account for these observations. A heightened awareness of the potential for neurologic involvement and further investigation into the relevant pathophysiology will be necessary to understand and ultimately mitigate SARS-CoV-2-associated neurologic injury.

Acute Symptomatic Seizures in Critically Ill Patients with COVID-19: Is There an Association?

Abstract: The coronavirus disease of 2019 (COVID-19) emerged as a global pandemic. Historically, the group of human coronaviruses can also affect the central nervous system leading to neurological symptoms; however, the causative mechanisms of the neurological manifestations of COVID-19 disease are not well known. Seizures have not been directly reported as a part of COVID-19 outside of patients with previously known brain injury or epilepsy. We report two cases of acute symptomatic seizures, in non-epileptic patients, associated with severe COVID-19 disease. Two advanced-age, non-epileptic, male patients presented to our northeast Ohio-based health system with concern for infection in Mid-March 2020. Both had a history of lung disease and during their hospitalization tested positive for SARS-CoV-2. They developed acute encephalopathy days into their hospitalization with clinical and electrographic seizures. Resolution of seizures was achieved with levetiracetam. Patients with COVID-19 disease are at an elevated risk for seizures, and the mechanism of these seizures is likely multifactorial. Clinical (motor) seizures may not be readily detected in this population due to the expansive utilization of sedatives and paralytics for respiratory optimization strategies. Many of these patients are also not electrographically monitored for seizures due to limited resources, multifactorial risk for acute encephalopathy, and the risk of cross-contamination. Previously, several neurological symptoms were seen in patients with more advanced COVID-19 disease, and these were thought to be secondary to multi-system organ failure and/or disseminated intravascular coagulopathy-related brain injury. However, these patients may also have an advanced breakdown of the blood–brain barrier precipitated by pro-inflammatory cytokine reactions. The neurotropic effect and neuroinvasiveness of SARS-Coronavirus-2 have not been directly established. Acute symptomatic seizures are possible in patients with COVID-19 disease. These seizures are likely multifactorial in origin, including cortical irritation due to blood–brain barrier breakdown, precipitated by the cytokine reaction as a part of the viral infection. Patients with clinical signs of seizures or otherwise unexplained encephalopathy may benefit from electroencephalography monitoring and/or empiric anti-epileptic therapy. Further studies are needed to elucidate the risk of seizures and benefit of monitoring in this population.

Anticoagulation use and Hemorrhagic Stroke in SARS-CoV-2 Patients Treated at a New York Healthcare System.

Abstract: While the thrombotic complications of COVID-19 have been well described, there are limited data on clinically significant bleeding complications including hemorrhagic stroke. The clinical characteristics, underlying stroke mechanism, and outcomes in this particular subset of patients are especially salient as therapeutic anticoagulation becomes increasingly common in the treatment and prevention of thrombotic complications of COVID-19. We conducted a retrospective cohort study of patients with hemorrhagic stroke (both non-traumatic intracerebral hemorrhage and spontaneous non-aneurysmal subarachnoid hemorrhage) who were hospitalized between March 1, 2020, and May 15, 2020, within a major healthcare system in New York, during the coronavirus pandemic. Patients with hemorrhagic stroke on admission and who developed hemorrhage during hospitalization were both included. We compared the clinical characteristics of patients with hemorrhagic stroke and COVID-19 to those without COVID-19 admitted to our hospital system between March 1, 2020, and May 15, 2020 (contemporary controls), and March 1, 2019, and May 15, 2019 (historical controls). Demographic variables and clinical characteristics between the individual groups were compared using Fischer’s exact test for categorical variables and nonparametric test for continuous variables. We adjusted for multiple comparisons using the Bonferroni method. During the study period in 2020, out of 4071 patients who were hospitalized with COVID-19, we identified 19 (0.5%) with hemorrhagic stroke. Of all COVID-19 with hemorrhagic stroke, only three had isolated non-aneurysmal SAH with no associated intraparenchymal hemorrhage. Among hemorrhagic stroke in patients with COVID-19, coagulopathy was the most common etiology (73.7%); empiric anticoagulation was started in 89.5% of these patients versus 4.2% in contemporary controls (p ≤ .001) and 10.0% in historical controls (p ≤ .001). Compared to contemporary and historical controls, patients with COVID-19 had higher initial NIHSS scores, INR, PTT, and fibrinogen levels. Patients with COVID-19 also had higher rates of in-hospital mortality (84.6% vs. 4.6%, p ≤ 0.001). Sensitivity analyses excluding patients with strictly subarachnoid hemorrhage yielded similar results. We observed an overall low rate of imaging-confirmed hemorrhagic stroke among patients hospitalized with COVID-19. Most hemorrhages in patients with COVID-19 infection occurred in the setting of therapeutic anticoagulation and were associated with increased mortality. Further studies are needed to evaluate the safety and efficacy of therapeutic anticoagulation in patients with COVID-19.

Cerebrovascular Autoregulation Monitoring in the Management of Adult Severe Traumatic Brain Injury: A Delphi Consensus of Clinicians

Abstract: Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty. To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities. A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants. Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence. The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.

Contusion Progression Following Traumatic Brain Injury: A Review of Clinical and Radiological Predictors, and Influence on Outcome.

Abstract: Secondary injuries remain an important cause of the morbidity and mortality associated with traumatic brain injury (TBI). Progression of cerebral contusions occurs in up to 75% of patients with TBI, and this contributes to subsequent clinical deterioration and requirement for surgical intervention. Despite this, the role of early clinical and radiological factors in predicting contusion progression remains relatively poorly defined due to studies investigating progression of all types of hemorrhagic injuries as a combined cohort. In this review, we summarize data from recent studies on factors which predict contusion progression, and the effect of contusion progression on clinical outcomes.

Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage.

Abstract: There are limited data on the risks and benefits of using andexanet alfa (AA) in comparison with four-factor prothrombin complex concentrate (4F-PCC) to reverse factor Xa inhibitors (FXi) associated intracranial hemorrhage (ICH). We sought to describe our experience with AA or 4F-PCC in patients with oral FXi-related traumatic and spontaneous ICH. We conducted a retrospective review of consecutive adult patients with FXi-related ICH who received AA or 4F-PCC. FXi-related ICH cases included traumatic and spontaneous intracranial hemorrhages. Our primary analysis evaluated ICH stability on head computed tomography scan (CT), defined as a similar amount of blood from the initial scan at the onset of ICH to subsequent scans, at 6-h and 24-h post-administration of AA or 4F-PCC. For the subset of spontaneous intraparenchymal hemorrhages, volume was measured at 6-h and 24-h post-reversal. In secondary analyses, we evaluated good functional outcome at discharge, defined as a Modified Rankin Score of less than 3, and the incidence of thrombotic events after AA or 4F-PCC adminstration, during hospitalization. A total of 44 patients (16 traumatic and 28 spontaneous ICH) with median age of 79 years [72–86], 36% females, with a FXi-related ICH, were included in this study. The majority of spontaneous ICHs were intraparenchymal 19 (68%). Twenty-eight patients (64%) received AA and 16 patients (36%) received 4F-PCC. There was no difference between AA and 4F-PCC in terms of CT stability at 6 h (21 [78%] vs 10 [71%], p = 0.71) and 24 h (15 [88%] vs 6 [60%], p = 0.15). In a subgroup of patients with spontaneous intraparenchymal hemorrhage, there was no difference in the degree of achieved hemostasis based on hematoma volume between AA and 4F-PCC at 6 h (9.3 mL [6.9–26.4] vs 10 mL [9.4–22.1], adjusted p = 0. 997) and 24-h (9.2 mL [6.1–18.8] vs 9.9 [9.4–21.1], adjusted p = 1). The number of patients with good outcome based on mRS on discharge were 10 (36%) and 6 (38%) in the AA and 4F-PCC groups, respectively (adjusted p = 0.81). The incidence of thromboembolic events was similar in the AA and 4F-PCC groups (2 [7%] vs 0, p = 0.53). In this limited sample of patients, we found no difference in neuroimaging stability, functional outcome and thrombotic events when comparing AA and 4F-PCC in patients with FXi-related ICH. Since our analysis is likely underpowered, a multi-center collaborative network devoted to this question is warranted.

Temporal Dynamics of ICP, CPP, PRx, and CPPopt in High-Grade Aneurysmal Subarachnoid Hemorrhage and the Relation to Clinical Outcome

Abstract: High intracranial pressure (ICP) and low cerebral perfusion pressure (CPP) may induce secondary brain injury following aneurysmal subarachnoid hemorrhage (aSAH). In the current study, we aimed to determine the temporal incidence of insults above/below certain ICP/CPP thresholds, the role of pressure autoregulation in CPP management (PRx and CPPopt), and the relation to clinical outcome. In this retrospective study, 242 patients were included with aSAH, who were treated in the neurointensive care unit, Uppsala University Hospital, Sweden, 2008–2018, with ICP monitoring the first 10 days post-ictus. Data from ICP, pressure autoregulation (PRx), CPP, and CPPopt (the CPP with the lowest/optimal PRx) were analyzed the first 10 days. The percentage of good monitoring time (GMT) above/below various ICP and CPP thresholds was calculated, e.g., ICP > 20 mm Hg (%), CPP < 60 mm Hg (%), and ∆CPPopt (CPP–CPPopt) < − 10 mm Hg (%). Of the 242 patients, 63 (26%) had favorable (GOS-E 5–8) and 179 (74%) had unfavorable (GOS-E 1–4) outcome at 12 months. Higher proportion (GMT) of ICP insults above 20 mm Hg was most common the first 3 days post-ictus and was then independently associated with unfavorable outcome. CPP gradually increased throughout the 10 days post-ictus, and higher proportion of GMT with CPP < 90 mm Hg was independently associated with unfavorable outcome in the late vasospasm phase (days 6.5–10). PRx was above 0 throughout the 10 days and deteriorated in the late vasospasm phase. Higher values were then independently associated with unfavorable outcome. There was no difference in GMT of CPP deviations from CPPopt between the outcome groups. Avoiding intracranial hypertension early and maintaining a high CPP in the vasospasm phase when the pressure autoregulation is most disturbed may improve clinical outcome after aSAH.

Proceedings of the First Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness

Abstract: 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.

Therapies to Restore Consciousness in Patients with Severe Brain Injuries: A Gap Analysis and Future Directions.

Abstract: 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. 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. 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. 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.

Catastrophic Intracranial Hemorrhage in Two Critically Ill Patients with COVID-19.

Abstract: Although the most common symptoms of COVID-19 are cough, fever, and anorexia, neurologic manifestations and complications have been observed, particularly among critically ill patients; these include headache, dizziness, encephalopathy, taste and smell impairment, seizures, and stroke [1, 2]. Here, we present two cases of patients with COVID-19 who developed catastrophic intracranial hemorrhage and cerebral edema.

Mechanisms Underlying Disorders of Consciousness: Bridging Gaps to Move Toward an Integrated Translational Science.

Abstract: In order to successfully detect, classify, prognosticate, and develop targeted therapies for patients with disorders of consciousness (DOC), it is crucial to improve our mechanistic understanding of how severe brain injuries result in these disorders. To address this need, the Curing Coma Campaign convened a Mechanisms Sub-Group of the Coma Science Work Group (CSWG), aiming to identify the most pressing knowledge gaps and the most promising approaches to bridge them. We identified a key conceptual gap in the need to differentiate the neural mechanisms of consciousness per se, from those underpinning connectedness to the environment and behavioral responsiveness. Further, we characterised three fundamental gaps in DOC research: (1) a lack of mechanistic integration between structural brain damage and abnormal brain function in DOC; (2) a lack of translational bridges between micro- and macro-scale neural phenomena; and (3) an incomplete exploration of possible synergies between data-driven and theory-driven approaches. In this white paper, we discuss research priorities that would enable us to begin to close these knowledge gaps. We propose that a fundamental step towards this goal will be to combine translational, multi-scale, and multimodal data, with new biomarkers, theory-driven approaches, and computational models, to produce an integrated account of neural mechanisms in DOC. Importantly, we envision that reciprocal interaction between domains will establish a “virtuous cycle,” leading towards a critical vantage point of integrated knowledge that will enable the advancement of the scientific understanding of DOC and consequently, an improvement of clinical practice.

Resting-State NIRS–EEG in Unresponsive Patients with Acute Brain Injury: A Proof-of-Concept Study

Abstract: Neurovascular-based imaging techniques such as functional MRI (fMRI) may reveal signs of consciousness in clinically unresponsive patients but are often subject to logistical challenges in the intensive care unit (ICU). Near-infrared spectroscopy (NIRS) is another neurovascular imaging technique but low cost, can be performed serially at the bedside, and may be combined with electroencephalography (EEG), which are important advantages compared to fMRI. Combined NIRS–EEG, however, has never been evaluated for the assessment of neurovascular coupling and consciousness in acute brain injury. We explored resting-state oscillations in eight-channel NIRS oxyhemoglobin and eight-channel EEG band-power signals to assess neurovascular coupling, the prerequisite for neurovascular-based imaging detection of consciousness, in patients with acute brain injury in the ICU (n = 9). Conscious neurological patients from step-down units and wards served as controls (n = 14). Unsupervised adaptive mixture-independent component analysis (AMICA) was used to correlate NIRS–EEG data with levels of consciousness and clinical outcome. Neurovascular coupling between NIRS oxyhemoglobin (0.07–0.13 Hz) and EEG band-power (1–12 Hz) signals at frontal areas was sensitive and prognostic to changing consciousness levels. AMICA revealed a mixture of five models from EEG data, with the relative probabilities of these models reflecting levels of consciousness over multiple days, although the accuracy was less than 85%. However, when combined with two channels of bilateral frontal neurovascular coupling, weighted k-nearest neighbor classification of AMICA probabilities distinguished unresponsive patients from conscious controls with > 90% accuracy (positive predictive value 93%, false discovery rate 7%) and, additionally, identified patients who subsequently failed to recover consciousness with > 99% accuracy. We suggest that NIRS–EEG for monitoring of acute brain injury in the ICU is worthy of further exploration. Normalization of neurovascular coupling may herald recovery of consciousness after acute brain injury.

Ancillary Testing for Determination of Death by Neurologic Criteria Around the World.

Abstract: We sought to identify similarities and differences in the diagnostic requirements for ancillary testing for determination of brain death/death by neurologic criteria (BD/DNC) around the world. We reviewed diagnostic requirements for ancillary testing for BD/DNC in 78 unique official national BD/DNC protocols obtained from contacts worldwide between January 2018 and April 2019. Details provided on the performance and interpretation of ancillary tests for determination of BD/DNC were variably provided and inconsistent. Approximately half of all protocols that included each ancillary test provided details about study performance: 63% of protocols that included conventional cerebral angiography, 55% of protocols that included electroencephalography, 50% of protocols that included somatosensory evoked potentials, 48% of protocols that included transcranial Doppler ultrasonography, 43% of protocols that included nuclear medicine flow study and 41% of protocols that included brainstem auditory evoked potentials. Similarly, about half of all protocols that included each ancillary test provided details about study interpretation: 66% of protocols that included electroencephalography, 59% of protocols that included brainstem auditory evoked potentials, 56% of protocols that included somatosensory evoked potentials, 55% of protocols that included transcranial Doppler ultrasonography, 52% of protocols that included conventional cerebral angiography and 49% of protocols that included nuclear medicine flow study. Diagnostic requirements for ancillary testing in BD/DNC determination vary around the world. We hope that the World Brain Death Project will improve worldwide consensus on the diagnostic requirements for ancillary testing in BD/DNC, both for performance and interpretation.

Intracerebral Hemorrhage in COVID-19 Patients with Pulmonary Failure: A Propensity Score-Matched Registry Study.

Abstract: Hypercoagulability in Coronavirus Disease 2019 (COVID-19) causes deep vein thrombosis and pulmonary embolism necessitating systemic anticoagulation. Case reports of intracerebral hemorrhages in ventilated COVID-19 patients warrant precaution. It is unclear, however, if COVID-19 patients with acute respiratory distress syndrome (ARDS) with or without veno-venous extracorporeal membrane oxygenation therapy (VV-ECMO) have more intracerebral hemorrhages (ICH) compared to other ARDS patients. We conducted a retrospective observational single-center study enrolling all patients with ARDS from 01/2018 to 05/2020. PCR-positive SARS-CoV-2 patients with ARDS were allocated to the COVID-19 group. Propensity score matching was performed for age, VV-ECMO, and bleeding risk. A total of 163 patients with moderate or severe ARDS were identified, 47 (28.8%) in the COVID-19 group, and 116 (71.2%) in the non-COVID-19 group. In 63/163 cases (38.7%), VV-ECMO therapy was required. The ICU survival was 52.8%. COVID-19 patients were older, more often male, and exhibited a lower SOFA score, but the groups showed similar rates of VV-ECMO therapy. Treatments with antiplatelet agents (p = 0.043) and therapeutic anticoagulation (p = 0.028) were significantly more frequent in the COVID-19 patients. ICH was detected in 22 patients (13.5%) with no statistical difference between the groups (11.2 vs. 19.1% without and with SARS-CoV-2, respectively, p = 0.21). Propensity score matching confirmed similar rates of ICH in both groups (12.8 vs. 19.1% without and with SARS-CoV-2, respectively, p = 0.57), thus leveling out possible confounders. Intracerebral hemorrhage was detected in every tenth patient with ARDS. Despite statistically higher rates of antiplatelet therapy and therapeutic anticoagulation in COVID-19 patients, we found a similar rate of ICH in patients with ARDS due to COVID-19 compared to other causes of ARDS.

The Limited Impact of Current Therapeutic Interventions on Cerebrovascular Reactivity in Traumatic Brain Injury: A Narrative Overview.

Abstract: Current intensive care unit (ICU) treatment strategies for traumatic brain injury (TBI) care focus on intracranial pressure (ICP)- and cerebral perfusion pressure (CPP)-directed therapeutics, dictated by guidelines. Impaired cerebrovascular reactivity in moderate/severe TBI is emerging as a major associate with poor outcome and appears to dominate the landscape of physiologic derangement over the course of a patient's ICU stay. Within this article, we review the literature on the known drivers of impaired cerebrovascular reactivity in adult TBI, highlight the current knowledge surrounding the impact of guideline treatment strategies on continuously monitored cerebrovascular reactivity, and discuss current treatment paradigms for impaired reactivity. Finally, we touch on the areas of future research, as we strive to develop specific therapeutics for impaired cerebrovascular reactivity in TBI. There exists limited literature to suggest advanced age, intracranial injury patterns of diffuse injury, and sustained ICP elevations may drive impaired cerebrovascular reactivity. To date, the literature suggests there is a limited impact of such ICP/CPP guideline-based therapies on cerebrovascular reactivity, with large portions of a given patients ICU period spent with impaired cerebrovascular reactivity. Emerging treatment paradigms focus on the targeting individualized CPP and ICP thresholds based on cerebrovascular reactivity, without directly targeting the pathways involved in its dysfunction. Further work involved in uncovering the molecular pathways involved in impaired cerebrovascular reactivity is required, so that we can develop therapeutics directed at its prevention and treatment.

Time Course of Hemostatic Disruptions After Traumatic Brain Injury: A Systematic Review of the Literature

Abstract: Almost two-thirds of patients with severe traumatic brain injury (TBI) develop some form of hemostatic disturbance, which contributes to poor outcome. While the initial head injury often leads to impaired clot formation, TBI is also associated with an increased risk of thrombosis. Most likely there is a progression from early bleeding to a later prothrombotic state. In this paper, we systematically review the literature on the time course of hemostatic disruptions following TBI. A MEDLINE search was performed for TBI studies reporting the trajectory of hemostatic assays over time. The search yielded 5,049 articles, of which 4,910 were excluded following duplicate removal as well as title and abstract review. Full-text assessment of the remaining articles yielded 33 studies that were included in the final review. We found that the first hours after TBI are characterized by coagulation cascade dysfunction and hyperfibrinolysis, both of which likely contribute to lesion progression. This is then followed by platelet dysfunction and decreased platelet count, the clinical implication of which remains unclear. Later, a poorly defined prothrombotic state emerges, partly due to fibrinolysis shutdown and hyperactive platelets. In the clinical setting, early administration of the antifibrinolytic agent tranexamic acid has proved effective in reducing head-injury-related mortality in a subgroup of TBI patients. Further studies evaluating the time course of hemostatic disruptions after TBI are warranted in order to identify windows of opportunity for potential treatment options.

Toxic Metabolic Encephalopathy in Hospitalized Patients with COVID-19.

Abstract: Toxic metabolic encephalopathy (TME) has been reported in 7–31% of hospitalized patients with coronavirus disease 2019 (COVID-19); however, some reports include sedation-related delirium and few data exist on the etiology of TME. We aimed to identify the prevalence, etiologies, and mortality rates associated with TME in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients. We conducted a retrospective, multicenter, observational cohort study among patients with reverse transcriptase–polymerase chain reaction-confirmed SARS-CoV-2 infection hospitalized at four New York City hospitals in the same health network between March 1, 2020, and May 20, 2020. TME was diagnosed in patients with altered mental status off sedation or after an adequate sedation washout. Patients with structural brain disease, seizures, or primary neurological diagnoses were excluded. The coprimary outcomes were the prevalence of TME stratified by etiology and in-hospital mortality (excluding comfort care only patients) assessed by using a multivariable time-dependent Cox proportional hazards models with adjustment for age, race, sex, intubation, intensive care unit requirement, Sequential Organ Failure Assessment scores, hospital location, and date of admission. Among 4491 patients with COVID-19, 559 (12%) were diagnosed with TME, of whom 435 of 559 (78%) developed encephalopathy immediately prior to hospital admission. The most common etiologies were septic encephalopathy (n = 247 of 559 [62%]), hypoxic-ischemic encephalopathy (HIE) (n = 331 of 559 [59%]), and uremia (n = 156 of 559 [28%]). Multiple etiologies were present in 435 (78%) patients. Compared with those without TME (n = 3932), patients with TME were older (76 vs. 62 years), had dementia (27% vs. 3%) or psychiatric history (20% vs. 10%), were more often intubated (37% vs. 20%), had a longer hospital length of stay (7.9 vs. 6.0 days), and were less often discharged home (25% vs. 66% [all P < 0.001]). Excluding comfort care patients (n = 267 of 4491 [6%]) and after adjustment for confounders, TME remained associated with increased risk of in-hospital death (n = 128 of 425 [30%] patients with TME died, compared with n = 600 of 3799 [16%] patients without TME; adjusted hazard ratio [aHR] 1.24, 95% confidence interval [CI] 1.02–1.52, P = 0.031), and TME due to hypoxemia conferred the highest risk (n = 97 of 233 [42%] patients with HIE died, compared with n = 631 of 3991 [16%] patients without HIE; aHR 1.56, 95% CI 1.21–2.00, P = 0.001). TME occurred in one in eight hospitalized patients with COVID-19, was typically multifactorial, and was most often due to hypoxemia, sepsis, and uremia. After we adjustment for confounding factors, TME was associated with a 24% increased risk of in-hospital mortality.

Continuous Monitoring of Cerebral Autoregulation in Children Supported by Extracorporeal Membrane Oxygenation: A Pilot Study

Abstract: Cerebral autoregulation (CA) impairment may pose a risk factor for neurological complications among children supported by extracorporeal membrane oxygenation (ECMO). Our first objective was to investigate the feasibility of CA continuous monitoring during ECMO treatment and to describe its evolution over time. The second objective was to analyze the association between CA impairment and neurological outcome. Observational prospective study. Twenty-nine children treated with veno-arterial or veno-venous ECMO in the PICU of Nantes University Hospital, France, and the PICU of the IRCCS Giannina Gaslini Institute in Genoa, Italy. A correlation coefficient between the variations of regional cerebral oxygen saturation and the variations of mean arterial blood pressure (MAP) was calculated as an index of CA (cerebral oxygenation reactivity index, COx). A COx > 0.3 was considered as indicative of autoregulation impairment. COx—MAP plots were investigated allowing determining optimal MAP (MAPopt) and limits of autoregulation: lower (LLA) and upper (ULA). Neurological outcome was assessed by the onset of an acute neurological event (ANE) after ECMO start. We included 29 children (median age 84 days, weight 4.8 kg). MAPopt, LLA, and ULA were detected in 90.8% (84.3–93.3) of monitoring time. Mean COx was significantly higher during day 1 of ECMO compared to day 2 [0.1 (0.02–0.15) vs. 0.01 (− 0.05 to 0.1), p = 0.002]. Twelve children experienced ANE (34.5%). The mean COx and the percentage of time spent with a COx > 0.3 were significantly higher among ANE+ compared to ANE− patients [0.09 (0.01–0.23) vs. 0.04 (− 0.02 to 0.06), p = 0.04 and 33.3% (24.8–62.1) vs. 20.8% (17.3–23.7) p = 0.001]. ANE+ patients spent significantly more time with MAP below LLA [17.2% (6.5–32.9) vs. 5.6% (3.6–9.9), p = 0.02] and above ULA [13% (5.3–38.4) vs. 4.2% (2.7–7.4), p = 0.004], respectively. CA assessment is feasible in pediatric ECMO. The first 24 h following ECMO represents the most critical period regarding CA. Impaired autoregulation is significantly more severe among patients who experience ANE.

Apnea Testing for the Determination of Brain Death: A Systematic Scoping Review

Abstract: Apnea is one of the three cardinal findings in brain death (BD). Apnea testing (AT) is physiologically and practically complex. We sought to review described modifications of AT, safety and complication rates, monitoring techniques, performance of AT on extracorporeal membrane oxygenation (ECMO), and other relevant considerations regarding AT. We conducted a systematic scoping review to answer these questions by searching the literature on AT in English language available in PubMed or EMBASE since 1980. Pediatric or animal studies were excluded. A total of 87 articles matched our inclusion criteria and were qualitatively synthesized in this review. A large body of the literature on AT since its inception addresses a variety of modifications, monitoring techniques, complication rates, ways to perform AT on ECMO, and other considerations such as variability in protocols, lack of uniform awareness, and legal considerations. Only some modifications are widely used, especially methods to maintain oxygenation, and most are not standardized or endorsed by brain death guidelines. Future updates to AT protocols and strive for unification of such protocols are desirable.

Toxicologic Confounders of Brain Death Determination: A Narrative Review.

Abstract: The aim of this narrative review is to describe the toxicologic confounders of brain death currently reported in the literature to offer guidance for physicians assessing brain death after a toxic exposure. We established an a priori definition of a "brain death mimic" as an unresponsive, intubated patient missing some, but not all brainstem reflexes. We completed a review of the literature utilizing MEDLINE and EMBASE to find case reports of patients of all ages in English, French, and Spanish meeting the criteria and hand searched the references of the results. We recorded xenobiotic dose, duration of physical exam suggesting brain death, and how the cases failed to meet full brain death criteria, when available. Fifty-six cases representing 19 different substances met the a priori definition of brain death mimic. Xenobiotic toxicities included: snake envenomation (13), baclofen (11), tricyclic antidepressants (8), bupropion (7), alcohols (4), antiepileptic agents (3), barbiturates (2), antidysrhythmics (2), organophosphates (2), and one case each of magnesium, succinylcholine, tetrodotoxin, and zolpidem. All patients except one survived to discharge and the majority at their baseline physical health. The most common means by which the cases failed brain death examination prerequisites was via normal neuroimaging. The xenobiotics in this review should be considered in cases of poisoning resulting in loss of brainstem reflexes and addressed before brain death determination. Brain death diagnosis should not be pursued in the setting of normal cerebral imaging or incomplete evaluation of brain death prerequisites.

Research Needs for Prognostic Modeling and Trajectory Analysis in Patients with Disorders of Consciousness

Abstract: The current state of the science regarding the care and prognosis of patients with disorders of consciousness is limited. Scientific advances are needed to improve the accuracy, relevance, and approach to prognostication, thereby providing the foundation to develop meaningful and effective interventions. To address this need, an interdisciplinary expert panel was created as part of the Coma Science Working Group of the Neurocritical Care Society Curing Coma Campaign. The panel performed a gap analysis which identified seven research needs for prognostic modeling and trajectory analysis (“recovery science”) in patients with disorders of consciousness: (1) to define the variables that predict outcomes; (2) to define meaningful intermediate outcomes at specific time points for different endotypes; (3) to describe recovery trajectories in the absence of limitations to care; (4) to harness big data and develop analytic methods to prognosticate more accurately; (5) to identify key elements and processes for communicating prognostic uncertainty over time; (6) to identify health care delivery models that facilitate recovery and recovery science; and (7) to advocate for changes in the health care delivery system needed to advance recovery science and implement already-known best practices. This report summarizes the current research available to inform the proposed research needs, articulates key elements within each area, and discusses the goals and advances in recovery science and care anticipated by successfully addressing these needs.

Biofluid Biomarkers in Traumatic Brain Injury: A Systematic Scoping Review.

Abstract: Emerging evidence suggests that biofluid-based biomarkers have diagnostic and prognostic potential in traumatic brain injuries (TBI). However, owing to the lack of a conceptual framework or comprehensive review, it is difficult to visualize the breadth of materials that might be available. We conducted a systematic scoping review to map and categorize the evidence regarding biofluid-based biochemical markers of TBI. A comprehensive search was undertaken in January 2019. Of 25,354 records identified through the literature search, 1036 original human studies were included. Five hundred forty biofluid biomarkers were extracted from included studies and classified into 19 distinct categories. Three categories of biomarkers including cytokines, coagulation tests, and nerve tissue proteins were investigated more than others and assessed in almost half of the studies (560, 515, and 502 from 1036 studies, respectively). S100 beta as the most common biomarker for TBI was tested in 21.2% of studies (220 articles). Cortisol was the only biomarker measured in blood, cerebrospinal fluid, urine, and saliva. The most common sampling time was at admission and within 24 h of injury. The included studies focused mainly on biomarkers from blood and central nervous system sources, the adult population, and severe and blunt injuries. The most common outcome measures used in studies were changes in biomarker concentration level, Glasgow coma scale, Glasgow outcome scale, brain computed tomography scan, and mortality rate. Biofluid biomarkers could be clinically helpful in the diagnosis and prognosis of TBI. However, there was no single definitive biomarker with accurate characteristics. The present categorization would be a road map to investigate the biomarkers of the brain injury cascade separately and detect the most representative biomarker of each category. Also, this comprehensive categorization could provide a guiding framework to design combined panels of multiple biomarkers.

A Precision Medicine Framework for Classifying Patients with Disorders of Consciousness: Advanced Classification of Consciousness Endotypes (ACCESS)

Abstract: 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. 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. 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. 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.

Prognostic Uncertainty in Critically Ill Patients with Traumatic Brain Injury: A Multicenter Qualitative Study.

Abstract: Prognostic uncertainty is frequently cited as a barrier to communication between physicians and patients and is particularly burdensome for surrogate decision-makers, who must make choices on behalf of their incapacitated family members. The Conceptual Taxonomy of Uncertainty is one model through which physician and surrogate communication can be analyzed to identify strategies for reducing uncertainty in surrogate decision-making. Our objective was to examine themes of uncertainty in physician communication of prognosis and surrogate goals-of-care decision-making for critically ill patients with traumatic brain injury (TBI). We performed a secondary analysis of a previous qualitative study that involved semistructured interviews of 16 surrogates of critically ill patients with TBI from two level 1 trauma centers and 20 TBI expert physicians from seven trauma centers. Open-ended questions about prognostic uncertainty were asked. We identified major themes with an inductive approach. The Conceptual Taxonomy of Uncertainty was applied to further characterize these themes as data-centered, system-centered, and patient-centered issues of uncertainty. Nearly all surrogates (15 of 16) and physicians (19 of 20) recognized the emotional burden of uncertainty in the decision-making process for surrogates. More than three quarters of surrogates (13 of 16) described instances in which a lack of information regarding their loved one’s disease or prognosis created uncertainty in their decision-making process, identifying both positive and negative instances of prognostic communication by physicians. We found that physicians used one of three strategies to communicate prognostic uncertainty to surrogates: leaving no room for uncertainty, honesty about uncertainty, and range of possibilities. These strategies did not meet the communication preferences of the majority of surrogates, with more than a third of decision-makers (6 of 15) being frustrated by too much ambiguity about prognosis as well as the failure to acknowledge the existence of uncertainty. We found that physician communication strategies rarely addressed surrogate needs regarding uncertainty adequately, suggesting an urgent need for future research into improved communication of prognostic uncertainty.

Intravenous Milrinone for Cerebral Vasospasm in Subarachnoid Hemorrhage: The MILRISPASM Controlled Before–After Study

Abstract: Intravenous (IV) milrinone, in combination with induced hypertension, has been proposed as a treatment option for cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). However, data on its safety and efficacy are scarce. This was a controlled observational study conducted in an academic hospital with prospectively and retrospectively collected data. Consecutive patients with cerebral vasospasm following aSAH and treated with both IV milrinone (0.5 µg/kg/min−1, as part of a strict protocol) and induced hypertension were compared with a historical control group receiving hypertension alone. Multivariable analyses aimed at minimizing potential biases. We assessed (1) 6-month functional disability (defined as a score between 2 and 6 on the modified Rankin Scale) and vasospasm-related brain infarction, (2) the rate of first-line or rescue endovascular angioplasty for vasospasm, and (3) immediate tolerance to IV milrinone. Ninety-four patients were included (41 and 53 in the IV milrinone and the control group, respectively). IV milrinone infusion was independently associated with a lower likelihood of 6-month functional disability (adjusted odds ratio [aOR] = 0.28, 95% confidence interval [CI] = 0.10–0.77]) and vasospasm-related brain infarction (aOR = 0.19, 95% CI 0.04–0.94). Endovascular angioplasty was less frequent in the IV milrinone group (6 [15%] vs. 28 [53%] patients, p = 0.0001, aOR = 0.12, 95% CI 0.04–0.38). IV milrinone (median duration of infusion, 5 [2–8] days) was prematurely discontinued owing to poor tolerance in 12 patients, mostly (n = 10) for “non/hardly-attained induced hypertension” (mean arterial blood pressure < 100 mmHg despite 1.5 µg/kg/min−1 of norepinephrine). However, this event was similarly observed in IV milrinone and control patients (n = 10 [24%] vs. n = 11 [21%], respectively, p = 0.68). IV milrinone was associated with a higher incidence of polyuria (IV milrinone patients had creatinine clearance of 191 [153–238] ml/min−1) and hyponatremia or hypokalemia, whereas arrhythmia, myocardial ischemia, and thrombocytopenia were infrequent. Despite its premature discontinuation in 29% of patients as a result of its poor tolerance, IV milrinone was associated with a lower rate of endovascular angioplasty and a positive impact on long-term neurological and radiological outcomes. These preliminary findings encourage the conduction of confirmatory randomized trials.

Determining Optimal Mean Arterial Pressure After Cardiac Arrest: A Systematic Review.

Abstract: The use of cerebral autoregulation monitoring to identify patient-specific optimal mean arterial pressure (MAPOPT) has emerged as a technique to augment cerebral oxygen delivery in post-cardiac arrest patients Our systematic review aims to determine (a) the average MAPOPT in these patients, (b) the feasibility of identifying MAPOPT, (c) the brain tissue oxygenation levels when MAP is within proximity to the MAPOPT and (d) the relationship between neurological outcome and MAPOPT-targeted resuscitation strategies We carried out this review in accordance with the PRISMA guidelines We included all studies that used cerebral autoregulation to determine MAPOPT in adult patients (> 16 years old) who achieved return of spontaneous circulation (ROSC) following cardiac arrest All studies had to include our primary outcome of MAPOPT We excluded studies where the patients had any history of traumatic brain injury, ischemic stroke or intracranial hemorrhage We identified six studies with 181 patients There was wide variability in cerebral autoregulation monitoring methods, length of monitoring, calculation and reporting of MAPOPT Amongst all studies, the median or mean MAPOPT was consistently above 65 mmHg (range 70–114 mmHg) Definitions of feasibility varied among studies and were difficult to summarize Only one study noted that brain tissue oxygenation increased as patients’ MAP approached MAPOPT There was no consistent association between targeting MAPOPT and improved neurological outcome There is considerable heterogeneity in MAPOPT due to differences in monitoring methods of autoregulation Further research is needed to assess the clinical utility of MAPOPT-guided strategies on decreasing secondary injury and improving neurological outcomes after ROSC

Hyperoxemia and Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage.

Abstract: Cerebral vasospasm is a major contributor to disability and mortality after aneurysmal subarachnoid hemorrhage. Oxidation of cell-free hemoglobin plays an integral role in neuroinflammation and is a suggested source of tissue injury after aneurysm rupture. This study sought to determine whether patients with subarachnoid hemorrhage and cerebral vasospasm were more likely to have been exposed to early hyperoxemia than those without vasospasm. This single-center retrospective cohort study included adult patients presenting with aneurysmal subarachnoid hemorrhage to Vanderbilt University Medical Center between January 2007 and December 2017. Patients with an ICD-9/10 diagnosis of aneurysmal subarachnoid hemorrhage were initially identified (N = 441) and subsequently excluded if they did not have intracranial imaging, arterial PaO2 values or died within 96 h post-rupture (N = 96). The final cohort was 345 subjects. The degree of hyperoxemia was defined by the highest PaO2 measured within 72 h after aneurysmal rupture. The primary outcome was development of cerebral vasospasm, which included asymptomatic vasospasm and delayed cerebral ischemia (DCI). Secondary outcomes were mortality and modified Rankin Scale. Three hundred and forty five patients met inclusion criteria; 218 patients (63%) developed vasospasm. Of those that developed vasospasm, 85 were diagnosed with delayed cerebral ischemia (DCI, 39%). The average patient age of the cohort was 55 ± 13 years, and 68% were female. Ninety percent presented with Fisher grade 3 or 4 hemorrhage (N = 310), while 42% presented as Hunt–Hess grade 4 or 5 (N = 146). In univariable analysis, patients exposed to higher levels of PaO2 by quintile of exposure had a higher mortality rate and were more likely to develop vasospasm in a dose-dependent fashion (P = 0.015 and P = 0.019, respectively). There were no statistically significant predictors that differentiated asymptomatic vasospasm from DCI and no significant difference in maximum PaO2 between these two groups. In multivariable analysis, early hyperoxemia was independently associated with vasospasm (OR = 1.15 per 50 mmHg increase in PaO2 [1.03, 1.28]; P = 0.013), but not mortality (OR = 1.10 [0.97, 1.25]; P = 0.147) following subarachnoid hemorrhage. Hyperoxemia within 72 h post-aneurysmal rupture is an independent predictor of cerebral vasospasm, but not mortality in subarachnoid hemorrhage. Hyperoxemia is a variable that can be readily controlled by adjusting the delivered FiO2 and may represent a modifiable risk factor for vasospasm.

Global characterisation of coagulopathy in isolated traumatic brain injury (iTBI): a CENTER-TBI analysis

Abstract: Trauma-induced coagulopathy in patients with traumatic brain injury (TBI) is associated with high rates of complications, unfavourable outcomes and mortality. The mechanism of the development of TBI-associated coagulopathy is poorly understood. This analysis, embedded in the prospective, multi-centred, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, aimed to characterise the coagulopathy of TBI. Emphasis was placed on the acute phase following TBI, primary on subgroups of patients with abnormal coagulation profile within 4 h of admission, and the impact of pre-injury anticoagulant and/or antiplatelet therapy. In order to minimise confounding factors, patients with isolated TBI (iTBI) (n = 598) were selected for this analysis. Haemostatic disorders were observed in approximately 20% of iTBI patients. In a subgroup analysis, patients with pre-injury anticoagulant and/or antiplatelet therapy had a twice exacerbated coagulation profile as likely as those without premedication. This was in turn associated with increased rates of mortality and unfavourable outcome post-injury. A multivariate analysis of iTBI patients without pre-injury anticoagulant therapy identified several independent risk factors for coagulopathy which were present at hospital admission. Glasgow Coma Scale (GCS) less than or equal to 8, base excess (BE) less than or equal to − 6, hypothermia and hypotension increased risk significantly. Consideration of these factors enables early prediction and risk stratification of acute coagulopathy after TBI, thus guiding clinical management.

Amantadine and Modafinil as Neurostimulants Following Acute Stroke: A Retrospective Study of Intensive Care Unit Patients.

Abstract: 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. 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. 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%). 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.