Mesenchymal Stem Cell Therapy in Acute Intracerebral Hemorrhage: A Dose-Escalation Safety and Tolerability Trial.

BACKGROUND: We conducted a preliminary phase I, dose-escalating, safety, and tolerability trial in the population of patients with acute intracerebral hemorrhage (ICH) by using human allogeneic bone marrow-derived mesenchymal stem/stromal cells. METHODS: Eligibility criteria included nontraumatic supratentorial hematoma less than 60 mL and Glasgow Coma Scale score greater than 5. All patients were monitored in the neurosciences intensive care unit for safety and tolerability of mesenchymal stem/stromal cell infusion and adverse events. We also explored the use of cytokines as biomarkers to assess responsiveness to the cell therapy. We screened 140 patients, enrolling 9 who met eligibility criteria into three dose groups: 0.5 million cells/kg, 1 million cells/kg, and 2 million cells/kg. RESULTS: Intravenous administration of allogeneic bone marrow-derived mesenchymal stem/stromal cells to treat patients with acute ICH is feasible and safe. CONCLUSIONS: Future larger randomized, placebo-controlled ICH studies are necessary to validate this study and establish the effectiveness of this therapeutic approach in the treatment of patients with ICH.

Balamuthia mandrillaris Encephalitis Presenting as a Symptomatic Focal Hypodensity in an Immunocompromised Patient.

We present the case of a 61-year-old woman with a history of orthotopic heart transplant who was hospitalized with new-onset headache. Magnetic resonance imaging (MRI) of the brain revealed T2 hyperintense signal involving the left occipital lobe with leptomeningeal enhancement and mild vasogenic edema. Initial neurologic examination was normal; however, after 7 days she developed imbalance, visual disturbances, night sweats, bradyphrenia, alexia without agraphia, and right hemianopsia. Brain MRI showed enlargement of the left occipital mass and worsening edema. Stereotactic needle biopsy showed nondiagnostic necrosis. The patient continued to deteriorate despite dexamethasone. Cerebrospinal fluid (CSF) suggested infection, and cytomegalovirus CSF polymerase chain reaction (PCR) was positive. The patient received vancomycin, imipenem, and ganciclovir. After obtaining a positive serum beta-D-glucan (Fungitell), amphotericin was added. Despite best medical efforts, the patient died. Postmortem broad-range PCR sequencing of the brain tissue was positive for rare amoeba Balamuthia mandrillaris.

Safety and Tolerability of Concentrated Intraventricular Nicardipine for Poor-Grade Aneurysmal Subarachnoid Hemorrhage-Related Vasospasm.

Objective: To report the preliminary safety, tolerability, and cerebral spinal fluid (CSF) sampling utility of serial injections of concentrated intraventricular nicardipine (IVN) in the treatment of aneurysmal subarachnoid hemorrhage (aSAH). Methods: We report the clinical, radiographic, and laboratory safety and tolerability data of a retrospective case series from a single academic medical center. All patients with aSAH developed vasospasm despite enteral nimodipine and received serial injections of concentrated IVN (2.5 mg/mL). CSF injection safety, tolerability, and utility are defined and reported. Results: A total of 59 doses of concentrated IVN were administered to three patients with poor-grade SAH. In Case 1, a 33-year-old man with modified Fisher scale (mFS) grade 4 and Hunt-Hess scale (HH) score 4 received 26 doses; in Case 2, a 36-year-old woman with mFS grade 4 and HH score 5 received 13 doses; and in Case 3, a 70-year-old woman with mFS grade 3 and HH score 4 received 20 doses. No major safety or tolerability events occurred. Two patients were discharged to a rehabilitation facility, and one died after discharge from the hospital. Conclusions: A concentrated 4 mg IVN dose (2.5 mg/mL) in a 1.6 mL injection appears relatively safe and tolerable and potentially offers a second-line strategy for treating refractory vasospasm in poor-grade SAH without compromising intracranial pressure or cerebral perfusion pressure.

Intravenous ravulizumab in mechanically ventilated patients hospitalised with severe COVID-19: a phase 3, multicentre, open-label, randomised controlled trial.

BACKGROUND: The complement pathway is a potential target for the treatment of severe COVID-19. We evaluated the safety and efficacy of ravulizumab, a terminal complement C5 inhibitor, in patients hospitalised with severe COVID-19 requiring invasive or non-invasive mechanical ventilation. METHODS: This phase 3, multicentre, open-label, randomised controlled trial (ALXN1210-COV-305) enrolled adult patients (aged ≥18 years) from 31 hospitals in France, Japan, Spain, the UK, and the USA. Eligible patients had a confirmed diagnosis of SARS-CoV-2 that required hospitalisation and either invasive or non-invasive mechanical ventilation, with severe pneumonia, acute lung injury, or acute respiratory distress syndrome confirmed by CT scan or x-ray. We randomly assigned participants (2:1) to receive intravenous ravulizumab plus best supportive care (BSC) or BSC alone using a web-based interactive response system. Randomisation was in permuted blocks of six with stratification by intubation status. Bodyweight-based intravenous doses of ravulizumab were administered on days 1, 5, 10, and 15. The primary efficacy endpoint was survival based on all-cause mortality at day 29 in the intention-to-treat (ITT) population. Safety endpoints were analysed in all randomly assigned patients in the ravulizumab plus BSC group who received at least one dose of ravulizumab, and in all randomly assigned patients in the BSC group. The trial is registered with ClinicalTrials.gov, NCT04369469, and was terminated at interim analysis due to futility. FINDINGS: Between May 10, 2020, and Jan 13, 2021, 202 patients were enrolled in the study and randomly assigned to ravulizumab plus BSC or BSC. 201 patients were included in the ITT population (135 in the ravulizumab plus BSC group and 66 in the BSC group). The ravulizumab plus BSC group comprised 96 (71%) men and 39 (29%) women with a mean age of 63·2 years (SD 13·23); the BSC group comprised 43 (65%) men and 23 (35%) women with a mean age of 63·5 years (12·40). Most patients (113 [84%] of 135 in the ravulizumab plus BSC group and 53 [80%] of 66 in the BSC group) were on invasive mechanical ventilation at baseline. Overall survival estimates based on multiple imputation were 58% for patients receiving ravulizumab plus BSC and 60% for patients receiving BSC (Mantel-Haenszel analysis: risk difference -0·0205; 95% CI -0·1703 to 0·1293; one-sided p=0·61). In the safety population, 113 (89%) of 127 patients in the ravulizumab plus BSC group and 56 (84%) of 67 in the BSC group had a treatment-emergent adverse event. Of these events, infections and infestations (73 [57%] vs 24 [36%] patients) and vascular disorders (39 [31%] vs 12 [18%]) were observed more frequently in the ravulizumab plus BSC group than in the BSC group. Five patients had serious adverse events considered to be related to ravulizumab. These events were bacteraemia, thrombocytopenia, oesophageal haemorrhage, cryptococcal pneumonia, and pyrexia (in one patient each). INTERPRETATION: Addition of ravulizumab to BSC did not improve survival or other secondary outcomes. Safety findings were consistent with the known safety profile of ravulizumab in its approved indications. Despite the lack of efficacy, the study adds value for future research into complement therapeutics in critical illnesses by showing that C5 inhibition can be accomplished in severely ill patients. FUNDING: Alexion, AstraZeneca Rare Disease.

Guillain-Barré Syndrome After Acute Hepatitis E Infection: A Case Report and Literature Review.

INTRODUCTION: Guillain-Barré syndrome precipitated by hepatitis E virus infection is rare, yet its incidence is increasing. CLINICAL FINDINGS: A 57-year-old man was transferred from another facility with fatigue, orange urine, and progressive weakness over 4 to 6 weeks. Initial laboratory results included total bilirubin, 9.0 mg/dL; direct bilirubin, 6.4 mg/dL; aspartate aminotransferase, 1551 U/L; alanine aminotransferase, 3872 U/L; and alkaline phosphatase, 430 U/L. Immunoglobulin M and quantitative polymerase chain reaction test results were positive for hepatitis E virus. Contrast-enhanced magnetic resonance imaging of the brain and spine showed no gross abnormalities. Analysis of cerebrospinal fluid obtained by lumbar puncture revealed the following (reference values in parentheses): total white blood cell count, 15/µL (0-5/µL), with 33% neutrophils and 54% lymphocytes; protein, 0.045 g/dL (0.015-0.045 g/dL); and glucose, 95 mg/dL (within reference range). Neurological examination revealed weakness in both upper extremities, with proximal strength greater than distal strength. The patient could not elevate either lower extremity off the bed and had areflexia and reduced sensation throughout all extremities. DIAGNOSIS: Guillain-Barré syndrome secondary to acute hepatitis E virus infection was diagnosed on the basis of clinical characteristics, serum and cerebrospinal fluid analyses, and nerve conduction studies. CONCLUSIONS: Nurses and clinicians should obtain a thorough history and consider hepatitis E virus infection as a precipitating factor in patients with sensory and motor disturbances consistent with Guillain-Barré syndrome. The case gives insight into the diagnostic process for Guillain-Barré syndrome and highlights the vital role of bedside nurses in evaluating and treating these patients.

Yield of Head Imaging in Ambulatory and Hospitalized Patients With SARS-CoV-2: A Multi-Center Study of 8675 Patients.

BACKGROUND AND PURPOSE: To describe the neurological and cerebrovascular findings in patients who tested positive for SARS-CoV-2 and underwent head imaging in ambulatory and inpatient settings. METHODS: Consecutive patients aged ≥18 years with SARS-CoV-2 infection diagnosed or treated at Mayo Clinic sites from 3/11/2020 to 7/23/2020 with head CT or brain MRI within 30 days of SARS-CoV-2 diagnosis were included. Demographics, medical history, indication for SARS-CoV-2 testing, neurologic symptoms, indication for brain imaging, neuroimaging findings, etiology of cerebrovascular events, and hospital course were abstracted from medical records. RESULTS: Of 8,675 patients with SARS-CoV-2, 180 (2.07%) had head imaging. Mean age of the entire cohort was 42 ± 18 years, whereas mean age of those with head imaging was 62 ± 19 years. Common indications for imaging were headache (34.4%), encephalopathy (33.4%), focal neurologic symptom (16.7%), and trauma (13.9%). While 86.1% of patients who underwent head imaging had normal exams, cerebrovascular events occurred in 18 patients (0.21% of the total cohort). Of patients with cerebrovascular events, 8 (44.5%) had acute infarct; 6 (33.3%), acute intracranial hemorrhage; 5 (2.8%), subacute infarct; and 1 (0.6%) posterior reversible encephalopathy syndrome. In the thirteen patients with ischemic stroke, 6 (46.2%) had cryptogenic stroke; 3 (23.1%), other defined causes; 2 (15.4%), small vessel stroke; 1 (7.7%), large vessel stroke; and 1 (7.7%) cardioembolic stroke. CONCLUSION: In ambulatory and hospitalized patients with SARS-CoV-2 infection, the rate of head imaging is low, with common indications of encephalopathy and headache. Cerebrovascular events occurred rarely, and cryptogenic stroke was the most common stroke mechanism.

C19TM: A nurse practitioner and physician assistant-led telemonitoring initiative ensures timely transfer of critically ill coronavirus disease 2019 patients.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic has required swift implementation of innovative practices in health care across the globe. We describe a nurse practitioner (NP) and physician assistant (PA)-led initiative to implement telemonitoring (TM) of noncritical patients with COVID-19 by critical care NPs and PAs (C19TM) for early detection of decompensation and early transfer to the intensive care unit (ICU). Every hospitalized patient with suspected or confirmed COVID-19 received an initial telemedicine consult with a critical care NP or PA. Patients were subsequently monitored via electronic health record once every 12-hour shift for the following indicators: oxygen modality and flow, increase in oxygen requirements, sustained tachypnea, and hemodynamic instability. If signs of decompensation were noted, the NP/PA would remotely reassess the patient, provide recommendations to the hospital internal medicine team, and transfer the patient to the ICU. The primary goal was to avoid cardiopulmonary deterioration requiring aerosol-generating procedures outside of the ICU. Over 65 days, 113 patients (86 suspected and 27 confirmed) were enrolled in C19TM. As a result, there were 13 transfers to the ICU, none of which required an aerosol-generating procedure outside of the ICU.

Reintubation Summation Calculation: A Predictive Score for Extubation Failure in Critically Ill Patients.

OBJECTIVE: To derive and validate a multivariate risk score for the prediction of respiratory failure after extubation. PATIENTS AND METHODS: We performed a retrospective cohort study of adult patients admitted to the intensive care unit from January 1, 2006, to December 31, 2015, who received mechanical ventilation for ≥48 h. Extubation failure was defined as the need for reintubation within 72 h after extubation. Multivariate logistic regression model coefficient estimates generated the Re-Intubation Summation Calculation (RISC) score. RESULTS: The 6,161 included patients were randomly divided into 2 sets: derivation (n = 3,080) and validation (n = 3,081). Predictors of extubation failure in the derivation set included body mass index <18.5 kg/m2 [odds ratio (OR), 1.91; 95% CI, 1.12-3.26; P = 0.02], threshold of Glasgow Coma Scale of at least 10 (OR, 1.68; 95% CI, 1.31-2.16; P < 0.001), mean airway pressure at 1 min of spontaneous breathing trial <10 cmH2O (OR, 2.11; 95% CI, 1.68-2.66; P < 0.001), fluid balance ≥1,500 mL 24 h preceding extubation (OR, 2.36; 95% CI, 1.87-2.96; P < 0.001), and total mechanical ventilation days ≥5 (OR, 3.94; 95% CI 3.04-5.11; P < 0.001). The C-index for the derivation and validation sets were 0.72 (95% CI, 0.70-0.75) and 0.72 (95% CI, 0.69-0.75). Multivariate logistic regression demonstrated that an increase of 1 in RISC score increased odds of extubation failure 1.6-fold (OR, 1.58; 95% CI, 1.47-1.69; P < 0.001). CONCLUSION: RISC predicts extubation failure in mechanically ventilated patients in the intensive care unit using several clinically relevant variables available in the electronic medical record but requires a larger validation cohort before widespread clinical implementation.

Anticoagulation in COVID-19: A Systematic Review, Meta-analysis, and Rapid Guidance From Mayo Clinic.

A higher risk of thrombosis has been described as a prominent feature of coronavirus disease 2019 (COVID-19). This systematic review synthesizes current data on thrombosis risk, prognostic implications, and anticoagulation effects in COVID-19. We included 37 studies from 4070 unique citations. Meta-analysis was performed when feasible. Coagulopathy and thrombotic events were frequent among patients with COVID-19 and further increased in those with more severe forms of the disease. We also present guidance on the prevention and management of thrombosis from a multidisciplinary panel of specialists from Mayo Clinic. The current certainty of evidence is generally very low and continues to evolve.

Creation of an optic nerve sheath diameter ultrasound model for NeuroICU education.

BACKGROUND: Using ultrasound to measure optic nerve sheath diameter (ONSD) is an emerging bedside technique to noninvasively assess intracranial pressure (ICP) in patients with brain injury. This technique is unique among bedside ultrasonography and is often performed by providers who have no formal ultrasound training. We sought to create a low-cost, 3D, reusable ONSD model to train neurology, neurosurgery, and critical care providers in measuring ICP. RESULTS: We identified 253 articles, of which 15 were associated with models and 2 with simulation. One gelatin model was reported, upon which we based our initial design. We could not validate the visual findings of this model; however, after constructing multiple beta models, the design most representative of human eye anatomy was a globe made of ballistics gel and either a 3 mm, 5 mm, or 7 mm × 50 mm 3D-printed optic nerve inserted into a platform composed of ballistics gel, all of which sat inside a 3D-printed skull. This model was used to teach ONSD measurements with ultrasound at a continuing medical education event prior to training on a live human model. CONCLUSION: A simple 3D ballistic ONSD model allows learners to practice proper hand placement and pressure, basic landmarks, and ONSD measurement prior to operating on a human eye. This model is replicable and sustainable given that the globe and platform are composed of ballistics gel.

A Combined Approach to Intracerebral Hemorrhage: Intravenous Mesenchymal Stem Cell Therapy with Minimally Invasive Hematoma Evacuation.

BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent stromal cells currently being tested as therapy for a variety of diseases. MSC therapy and hematoma evacuation using a minimally invasive approach are being studied separately to improve clinical outcomes after stroke. We report the first case of a patient with intracerebral hemorrhage (ICH) treated with combination MSC therapy and endoscopic hematoma evacuation. CASE REPORT: A 36-year-old woman with a past medical history of essential chronic hypertension and right lung bronchial atresia presented to the emergency department with acute neurologic decline (National Institute of Health Stroke Scale [NIHSS] score, 22). Computed tomography showed a 4.4 × 3.5 × 3.5 cm right basal ganglia hemorrhage with intraventricular extension. An external ventricular drain was placed, and she was enrolled in a Phase I clinical trial investigating intravenous MSC therapy for acute ICH. Continued neurologic deterioration due to increased intracranial pressure led to minimally invasive hematoma evacuation using the Artemis Neuro Evacuation Device (Penumbra, Inc.) on hospital day 4. Follow-up scans showed decreased density and extent of hemorrhage. She was discharged on day 41 with improved neurologic function scores (NIHSS score, 2). At 3-month follow-up, she was walking on her own, but had residual left arm and hand weakness (modified Rankin Score, 2). CONCLUSIONS: This case report suggests that the combination of MSC therapy and minimally invasive hematoma evacuation may be safe and well tolerated. Further larger randomized clinical trials are required to identify whether MSC therapy in combination with minimally invasive hematoma evacuation is safe, tolerable, and potentially improves outcomes than either alone.

Early Bortezomib Therapy for Refractory Anti-NMDA Receptor Encephalitis.

Introduction: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an increasingly recognized form of immune-mediated encephalitis. Here we present a case that represents the shortest hospitalization-to-bortezomib treatment timeline (42 days), and we believe that this is reflected in the patient's outcome with complete independence within a short timeframe. Case Report: We describe a case of anti-NMDA receptor encephalitis in an 18-year-old African American female presenting with progressive, medically refractory disease. Despite two rounds of high-dose intravenous steroids, plasma exchange, immunoglobulin administration, and rituximab for B-cell depletion, the patient failed to respond by hospital day 42 and received off-label use of the proteasome inhibitor bortezomib. During the 15 days after the bortezomib administration, the patient showed dramatic neurologic recovery that allowed her transfer out of the intensive care unit. At follow-up after 1-month, the patient reported feeling normal cognitively and showed dramatic improvement in cognitive scores. Conclusion: This case and literature review provide preliminary evidence that early treatment of anti-NMDA receptor encephalitis with the proteasome inhibitor bortezomib appears safe and tolerable. However, randomized trials are needed to show the efficacy and the long-term benefit.

Cerebrospinal meningitis: a global disease with regional variability?

INTRODUCTION: In this edition, Szymanski et al. present the results of their retrospective study of the clinical differences between patients with meningococcal meningitis and pneumococcal cerebrospinal meningitis at the Regional Specialistic Hospital in Wroclaw, Poland. CLINICAL REFLECTIONS: The authors found that compared to patients with N. meningitidis, patients with S. pneumoniae were older, more frequently had chronic comorbidities, and had higher rates of pneumonia, longer hospitalisations, and higher mortality. Patients with N. meningitidis had higher rates of haemorrhagic rash and DIC. CLINICAL IMPLICATIONS: These characteristics and outcomes reflect previous reports from Western Europe and the United States.

Incorporation of Telestroke into Neurology Residency Training: "Time Is Brain and Education".

Background: With increasing demand for neurologists, nontraditional health care delivery mechanisms have been developed to leverage this limited resource. Introduction: Telemedicine has emerged as an effective digital solution. Over the past three decades, telemedicine use has steadily grown; however, neurologists often learn on the job, rather than as part of their medical training. The current literature regarding telestroke training during neurology training is sparse, focusing on cerebrovascular fellowship curricula. We sought to enhance telestroke training in our neurology residency by incorporating real-life application. Materials and Methods: We implemented a formal educational model for neurology residents to use telemedicine for remote acquisition of the National Institutes of Health Stroke Scale (NIHSS) for patients with suspected acute ischemic stroke (AIS) before arrival at our comprehensive stroke center. This three-phase educational model involved multidisciplinary classroom didactics, simulation exercises, and real-world experience. Training and feedback were provided by neurologists experienced in telemedicine. Results: All residents completed formal training in telemedicine prehospital NIHSS acquisition and had the opportunity to participate in additional simulation exercises. Currently, residents are gaining additional experience by performing prehospital NIHSS acquisition for patients in whom AIS is suspected. Our preliminary data indicate that resident video encounters average 10.6 min in duration, thus saving time once patients arrive at our hospital. Discussion: To our knowledge, this is the first report of a telestroke-integrated neurology residency program in a comprehensive stroke center resulting in shortened time to treatment in patients with suspected AIS. Conclusions: We present a model that can be adopted by other neurology residency programs as it provides real-world telemedicine training critical to future neurologists.

Ketamine in seizure management and future pharmacogenomic considerations.

Ketamine is a noncompetitive N-methyl-D-aspartate antagonist with emerging evidence for use in medically refractory epilepsy. We describe the novel use of low-dose intravenous (IV) ketamine transitioning to enteral formulation in a patient with drug-resistant localization-related refractory epilepsy. We performed a National Library of Medicine (NLM) literature review using search terms "ketamine", "low dose", and "seizure" for similar cases, followed by an illustrative clinical case. Our NLM search engine methodology yielded 24 hits, none of which described use of low-dose ketamine for seizures. Anesthetic doses are used for status epilepticus, but we show that in a patient with postoperative worsening of his chronic seizure burden, low-dose IV ketamine can be used to avoid oversedation and intubation. We demonstrate that IV ketamine can be transitioned to oral regimen to shorten length of stay in the intensive care unit and hospital and has future CYP2B6 pharmacogenomic considerations for further dose individualization.

Acute bacterial meningitis and stroke.

INTRODUCTION: Acute bacterial meningitis remains a common disease, especially in developing countries. Although advances over the last century have improved mortality and morbidity, the neurological adverse effects remain high. Specifically, acute ischaemic stroke is a serious comorbidity that represents both disease severity and poor prognosis. This review presents the clinical connection between meningitis and stroke, and discusses the neuroinflammatory components that have direct ties between these diseases. STATE OF THE ART: Ischaemic stroke is the direct result of the inflammatory response produced to eradicate infectious pathogens. Bacterial virulence factors and pathogen-associated molecular patterns cause direct damage to the blood-brain barrier and trigger leukocytes to react to the infection. Cytokines are released that cause further destruction of the blood-brain barrier, lead to neuronal death, and recruit the prothrombotic effects of the coagulation cascade through the complement system. Unfortunately, this inflammatory response causes vasculopathy and hypercoagulation of the cerebral blood vessels, leading to cerebral ischaemia. CLINICAL IMPLICATIONS: Pharmacological attempts to mitigate this inflammatory response have produced both positive and negative results. On the one hand, corticosteroids have been shown to improve mortality if given early in patients with bacterial meningitis, particularly pneumococcal meningitis. On the other hand, corticosteroids have been linked to delayed cerebral infarction and other adverse effects. FUTURE DIRECTIONS: New targets for specific inflammatory markers have shown success in rodent models, but have not yet been proven beneficial in humans. Genetic markers are on the horizon, and may serve as individualised targets for diagnosis and therapy.

Reducing Door-to-Reperfusion Time for Mechanical Thrombectomy With a Multitiered Notification System for Acute Ischemic Stroke.

OBJECTIVE: To reduce door-to-angiographic reperfusion (DTR) time to 120 minutes for patients presenting with acute ischemic stroke attributed to anterior circulation large-vessel occlusion amenable to endovascular mechanical thrombectomy. PATIENTS AND METHODS: Patients treated with mechanical thrombectomy before (April 10, 2015, through April 11, 2016) and after (April 12, 2016, through May 10, 2017) implementation of a multitiered notification system were studied. Lean process mapping was used to assess inefficiencies with multidisciplinary triage. A 3-tiered paging platform, which rapidly alerts essential personnel of the acute ischemic stroke team at advancing decision points, was introduced. RESULTS: Sixty-two patients were analyzed before and after implementation (34 vs 28, respectively). Following intervention, DTR time was reduced by 43 minutes (mean DTR, 170 minutes vs 127 minutes; P=.02). At 90-day follow up, 5 of the 28 patients in the postintervention cohort (19%) had excellent neurologic outcomes, defined as a modified Rankin Scale score of 0, compared to 0 of 34 (0%) in the preintervention cohort (P=.89). Reductions were also seen in the length of stay on the neurocritical care service (mean, 6 vs 3 days; P=.006), and total hospital charges for combined groups (mean, $100,083 vs $161,458; P<.001). CONCLUSION: The multitiered notification system was a feasible solution for improving DTR within our institution, resulting in reductions of overall DTR time, neurocritical care service length of stay, and total hospital charges.