Common Data Element for Disorders of Consciousness: Recommendations from the Working Group on Therapeutic Interventions.

BACKGROUND: Over the past 30 years, there have been significant advances in the understanding of the mechanisms associated with loss and recovery of consciousness following severe brain injury. This work has provided a strong grounding for the development of novel restorative therapeutic interventions. Although all interventions are aimed at modulating and thereby restoring brain function, the landscape of existing interventions encompasses a very wide scope of techniques and protocols. Despite vigorous research efforts, few approaches have been assessed with rigorous, high-quality randomized controlled trials. As a growing number of exploratory interventions emerge, it is paramount to develop standardized approaches to reporting results. The successful evaluation of novel interventions depends on implementation of shared nomenclature and infrastructure. To address this gap, the Neurocritical Care Society's Curing Coma Campaign convened nine working groups and charged them with developing common data elements (CDEs). Here, we report the work of the Therapeutic Interventions Working Group. METHODS: The working group reviewed existing CDEs relevant to therapeutic interventions within the National Institutes of Health National Institute of Neurological Disorders and Stroke database and reviewed the literature for assessing key areas of research in the intervention space. CDEs were then proposed, iteratively discussed and reviewed, classified, and organized in a case report form (CRF). RESULTS: We developed a unified CRF, including CDEs and key design elements (i.e., methodological or protocol parameters), divided into five sections: (1) patient information, (2) general study information, (3) behavioral interventions, (4) pharmacological interventions, and (5) device interventions. CONCLUSIONS: The newly created CRF enhances systematization of future work by proposing a portfolio of measures that should be collected in the development and implementation of studies assessing novel interventions intended to increase the level of consciousness or rate of recovery of consciousness in patients with disorders of consciousness.

Impact of Therapeutic Interventions on Cerebral Autoregulatory Function Following Severe Traumatic Brain Injury: A Secondary Analysis of the BOOST-II Study.

BACKGROUND: The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II randomized controlled trial used a tier-based management protocol based on brain tissue oxygen (PbtO2) and intracranial pressure (ICP) monitoring to reduce brain tissue hypoxia after severe traumatic brain injury. We performed a secondary analysis to explore the relationship between brain tissue hypoxia, blood pressure (BP), and interventions to improve cerebral perfusion pressure (CPP). We hypothesized that BP management below the lower limit of autoregulation would lead to cerebral hypoperfusion and brain tissue hypoxia that could be improved with hemodynamic augmentation. METHODS: Of the 119 patients enrolled in the Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II trial, 55 patients had simultaneous recordings of arterial BP, ICP, and PbtO2. Autoregulatory function was measured by interrogating changes in ICP and PbtO2 in response to fluctuations in CPP using time-correlation analysis. The resulting autoregulatory indices (pressure reactivity index and oxygen reactivity index) were used to identify the "optimal" CPP and limits of autoregulation for each patient. Autoregulatory function and percent time with CPP outside personalized limits of autoregulation were calculated before, during, and after all interventions directed to optimize CPP. RESULTS: Individualized limits of autoregulation were computed in 55 patients (mean age 38 years, mean monitoring time 92 h). We identified 35 episodes of brain tissue hypoxia (PbtO2 < 20 mm Hg) treated with CPP augmentation. Following each intervention, mean CPP increased from 73 ± 14 mm Hg to 79 ± 17 mm Hg (p = 0.15), and mean PbtO2 improved from 18.4 ± 5.6 mm Hg to 21.9 ± 5.6 mm Hg (p = 0.01), whereas autoregulatory function trended toward improvement (oxygen reactivity index 0.42 vs. 0.37, p = 0.14; pressure reactivity index 0.25 vs. 0.21, p = 0.2). Although optimal CPP and limits remained relatively unchanged, there was a significant decrease in the percent time with CPP below the lower limit of autoregulation in the 60 min after compared with before an intervention (11% vs. 23%, p = 0.05). CONCLUSIONS: Our analysis suggests that brain tissue hypoxia is associated with cerebral hypoperfusion characterized by increased time with CPP below the lower limit of autoregulation. Interventions to increase CPP appear to improve autoregulation. Further studies are needed to validate the importance of autoregulation as a modifiable variable with the potential to improve outcomes.

Temperature Control in the Era of Personalized Medicine: Knowledge Gaps, Research Priorities, and Future Directions.

Hypoxic-ischemic brain injury (HIBI) is the leading cause of death and disability after cardiac arrest. To date, temperature control is the only intervention shown to improve neurologic outcomes in patients with HIBI. Despite robust preclinical evidence supporting hypothermia as neuroprotective therapy after cardiac arrest, there remains clinical equipoise regarding optimal core temperature, therapeutic window, and duration of therapy. Current guidelines recommend continuous temperature monitoring and active fever prevention for at least 72 h and additionally note insufficient evidence regarding temperature control targeting 32 °C-36 °C. However, population-based thresholds may be inadequate to support the metabolic demands of ischemic, reperfused, and dysregulated tissue. Promoting a more personalized approach with individualized targets has the potential to further improve outcomes. This review will analyze current knowledge and evidence, address research priorities, explore the components of high-quality temperature control, and define critical future steps that are needed to advance patient-centered care for cardiac arrest survivors.

Detection of Intracerebral Hemorrhage Using Low-Field, Portable Magnetic Resonance Imaging in Patients With Stroke.

BACKGROUND: Neuroimaging is essential for detecting spontaneous, nontraumatic intracerebral hemorrhage (ICH). Recent data suggest ICH can be characterized using low-field magnetic resonance imaging (MRI). Our primary objective was to investigate the sensitivity and specificity of ICH on a 0.064T portable MRI (pMRI) scanner using a methodology that provided clinical information to inform rater interpretations. As a secondary aim, we investigated whether the incorporation of a deep learning (DL) reconstruction algorithm affected ICH detection. METHODS: The pMRI device was deployed at Yale New Haven Hospital to examine patients presenting with stroke symptoms from October 26, 2020 to February 21, 2022. Three raters independently evaluated pMRI examinations. Raters were provided the images alongside the patient's clinical information to simulate real-world context of use. Ground truth was the closest conventional computed tomography or 1.5/3T MRI. Sensitivity and specificity results were grouped by DL and non-DL software to investigate the effects of software advances. RESULTS: A total of 189 exams (38 ICH, 89 acute ischemic stroke, 8 subarachnoid hemorrhage, 3 primary intraventricular hemorrhage, 51 no intracranial abnormality) were evaluated. Exams were correctly classified as positive or negative for ICH in 185 of 189 cases (97.9% overall accuracy). ICH was correctly detected in 35 of 38 cases (92.1% sensitivity). Ischemic stroke and no intracranial abnormality cases were correctly identified as blood-negative in 139 of 140 cases (99.3% specificity). Non-DL scans had a sensitivity and specificity for ICH of 77.8% and 97.1%, respectively. DL scans had a sensitivity and specificity for ICH of 96.6% and 99.3%, respectively. CONCLUSIONS: These results demonstrate improvements in ICH detection accuracy on pMRI that may be attributed to the integration of clinical information in rater review and the incorporation of a DL-based algorithm. The use of pMRI holds promise in providing diagnostic neuroimaging for patients with ICH.

Brain imaging with portable low-field MRI.

The advent of portable, low-field MRI (LF-MRI) heralds new opportunities in neuroimaging. Low power requirements and transportability have enabled scanning outside the controlled environment of a conventional MRI suite, enhancing access to neuroimaging for indications that are not well suited to existing technologies. Maximizing the information extracted from the reduced signal-to-noise ratio of LF-MRI is crucial to developing clinically useful diagnostic images. Progress in electromagnetic noise cancellation and machine learning reconstruction algorithms from sparse k-space data as well as new approaches to image enhancement have now enabled these advancements. Coupling technological innovation with bedside imaging creates new prospects in visualizing the healthy brain and detecting acute and chronic pathological changes. Ongoing development of hardware, improvements in pulse sequences and image reconstruction, and validation of clinical utility will continue to accelerate this field. As further innovation occurs, portable LF-MRI will facilitate the democratization of MRI and create new applications not previously feasible with conventional systems.

Development and validation of a novel score to predict brain death after out-of-hospital cardiac arrest.

BACKGROUND AND OBJECTIVES: Brain death (BD) occurs in 9-24% of successfully resuscitated out-of-hospital cardiac arrests (OHCA). To predict BD after OHCA, we developed a novel brain death risk (BDR) score. METHODS: We identified independent predictors of BD after OHCA in a retrospective, single academic center cohort between 2011 and 2021. The BDR score ranges from 0 to 7 points and includes: non-shockable rhythm (1 point), drug overdose as etiology of arrest (1 point), evidence of grey-white differentiation loss or sulcal effacement on head computed tomography (CT) radiology report within 24 hours of arrest (2 points), Full-Outline-Of-UnResponsiveness (FOUR) score of 0 (2 points), FOUR score 1-5 (1 point), and age <45 years (1 point). We internally validated the BDR score using k-fold cross validation (k = 8) and externally validated the score at an independent academic center. The main outcome was BD. RESULTS: The development cohort included 362OHCA patients, of whom 18% (N = 58) experienced BD. Internal validation provided an area under the receiving operator characteristic curve (AUC) (95% CI) of 0.931 (0.905-0.957). In the validation cohort, 19.8% (N = 17) experienced BD. The AUC (95% CI) was 0.849 (0.765-0.933). In both cohorts, a BDR score >4 was the optimal cut off (sensitivity 0.903 and 0.882, specificity 0.830 and 0.652, in the development and validation cohorts respectively). DISCUSSION: The BDR score identifies those at highest risk for BD after OHCA. Our data suggest that a BDR score >4 is the optimal cut off.

Validation of the rCAST score and comparison to the PCAC and FOUR scores for prognostication after out-of-hospital cardiac arrest.

AIM: Early, accurate outcome prediction after out-of-hospital cardiac arrest (OHCA) is critical for clinical decision-making and resource allocation. We sought to validate the revised post-Cardiac Arrest Syndrome for Therapeutic hypothermia (rCAST) score in a United States cohort and compare its prognostic performance to the Pittsburgh Cardiac Arrest Category (PCAC) and Full Outline of UnResponsiveness (FOUR) scores. METHODS: This is a single-center, retrospective study of OHCA patients admitted between January 2014-August 2022. Area under the receiver operating curve (AUC) was computed for each score for predicting poor neurologic outcome at discharge and in-hospital mortality. We compared the scores' predictive abilities via Delong's test. RESULTS: Of 505 OHCA patients with all scores available, the medians [IQR] for rCAST, PCAC, and FOUR scores were 9.5 [6.0, 11.5], 4 [3, 4], and 2 [0, 5], respectively. The AUC [95% confidence interval] of the rCAST, PCAC, and FOUR scores for predicting poor neurologic outcome were 0.815 [0.763-0.867], 0.753 [0.697-0.809], and 0.841 [0.796-0.886], respectively. The AUC [95% confidence interval] of the rCAST, PCAC, and FOUR scores for predicting mortality were 0.799 [0.751-0.847], 0.723 [0.673-0.773], and 0.813 [0.770-0.855], respectively. The rCAST score was superior to the PCAC score for predicting mortality (p = 0.017). The FOUR score was superior to the PCAC score for predicting poor neurological outcome (p < 0.001) and mortality (p < 0.001). CONCLUSION: The rCAST score can reliably predict poor outcome in a United States cohort of OHCA patients regardless of TTM status and outperforms the PCAC score.

Brain imaging after cardiac arrest.

PURPOSE OF REVIEW: Many patients who survive a cardiac arrest have a disorder of consciousness in the period after resuscitation, and prediction of long-term neurologic outcome requires multimodal assessments. Brain imaging with computed tomography (CT) and MRI is a key component. We aim to provide an overview of the types of neuroimaging available and their uses and limitations. RECENT FINDINGS: Recent studies have evaluated qualitative and quantitative techniques to analyze and interpret CT and MRI to predict both good and poor outcomes. Qualitative interpretation of CT and MRI is widely available but is limited by low inter-rater reliability and lack of specificity around which findings have the highest correlation with outcome. Quantitative analysis of CT (gray-white ratio) and MRI (amount of brain tissue with an apparent diffusion coefficient below certain thresholds) hold promise, though additional research is needed to standardize the approach. SUMMARY: Brain imaging is important for evaluating the extent of neurologic injury after cardiac arrest. Future work should focus on addressing previous methodological limitations and standardizing approaches to qualitative and quantitative imaging analysis. Novel imaging techniques are being developed and new analytical methods are being applied to advance the field.

Emergent external ventricular drain placement in patients with factor Xa inhibitor-associated intracerebral hemorrhage after reversal with andexanet alfa.

BACKGROUND: Andexanet alfa (AA), a factor Xa-inhibitor (FXi) reversal agent, is given as a bolus followed by a 2-hour infusion. This long administration time can delay EVD placement in intracerebral hemorrhage (ICH) patients. We sought to evaluate the safety of EVD placement immediately post-AA bolus compared to post-AA infusion. METHODS: We conducted a retrospective study that included adult patients admitted with FXi-associated ICH who received AA and underwent EVD placement The primary outcome was the occurrence of a new hemorrhage (tract, extra-axial, or intraventricular hemorrhage). Secondary outcomes included mortality, intensive care unit and hospital length of stay, and discharge modified Rankin Score. The primary safety outcome was documented thrombotic events. RESULTS: Twelve patients with FXi related ICH were included (EVD placement post-AA bolus, N = 8; EVD placement post-AA infusion, N = 4). Each arm included one patient with bilateral EVD placed. There was no difference in the incidence of new hemorrhages, with one post-AA bolus patient had small, focal, nonoperative extra-axial hemorrhage. Morbidity and mortality were higher in post-AA infusion patients (mRS, post-AA bolus, 4 [4-6] vs. post-AA infusion 6 [5,6], p = 0.24 and post-AA bolus, 3 (37.5 %) vs. post-AA infusion, 3 (75 %), p = 0.54, respectively). One patient in the post-AA bolus group had thrombotic event. There was no difference in hospital LOS (post-AA bolus, 19 days [12-26] vs. post-AA infusion, 14 days [9-22], p = 0.55) and ICU LOS (post-AA bolus, 10 days [6-13] vs. post-AA infusion, 11 days [5-21], p = 0.86). CONCLUSION: We report no differences in the incidence of tract hemorrhage, extra-axial hemorrhage, or intraventricular hemorrhage post-AA bolus versus post-AA infusion. Larger prospective studies to validate these results are warranted.

Future of Neurology & Technology: Neuroimaging Made Accessible Using Low-Field, Portable MRI.

In the 20th century, the advent of neuroimaging dramatically altered the field of neurologic care. However, despite iterative advances since the invention of CT and MRI, little progress has been made to bring MR neuroimaging to the point of care. Recently, the emergence of a low-field (<1 T) portable MRI (pMRI) is setting the stage to revolutionize the landscape of accessible neuroimaging. Users can transport the pMRI into a variety of locations, using a standard 110-220 V wall outlet. In this article, we discuss current applications for pMRI, including in the acute and critical care settings, the barriers to broad implementation, and future opportunities.

Oxygen Supplementation and Hyperoxia in Critically Ill Cardiac Patients: From Pathophysiology to Clinical Practice.

Oxygen supplementation has been a mainstay in the management of patients with acute cardiac disease. While hypoxia is known to be detrimental, the adverse effects of artificially high oxygen levels (hyperoxia) have only recently been recognized. Hyperoxia may induce harmful hemodynamic effects, including peripheral and coronary vasoconstriction, and direct cellular toxicity through the production of reactive oxygen species. In addition, emerging evidence has shown that hyperoxia is associated with adverse clinical outcomes. Thus, it is essential for the cardiac intensive care unit (CICU) clinician to understand the available evidence and titrate oxygen therapies to specific goals. This review summarizes the pathophysiology of oxygen within the cardiovascular system and the association between supplemental oxygen and hyperoxia in patients with common CICU diagnoses, including acute myocardial infarction, heart failure, shock, cardiac arrest, pulmonary hypertension, and respiratory failure. Finally, we highlight lessons learned from available trials, gaps in knowledge, and future directions.

Emergency department initiated resuscitative endovascular balloon occlusion of the aorta (REBOA) for out-of-hospital cardiac arrest is feasible and associated with improvements in end-tidal carbon dioxide.

Objectives: Out-of-hospital cardiac arrest (OHCA) claims the lives of approximately 350,000 people in the United States each year. Resuscitative endovascular balloon occlusion of the aorta (REBOA) when used as an adjunct to advanced cardiac life support may improve cardio-cerebral perfusion. Our primary research objective was to determine the feasibility of emergency department (ED)-initiated REBOA for OHCA patients in an academic urban ED. Methods: This was a single-center, single-arm, early feasibility trial that used REBOA as an adjunct to advanced cardiac life support (ACLS) in OHCA. Subjects under 80 years with witnessed OHCA and who received cardiopulmonary rescuitation (CPR) within 6 minutes were eligible. Results: Five patients were enrolled between February 2020 and April 2021. The procedure was successful in all patients and 4 of 5 (80%) patients had transient return of spontaneous circulation (ROSC) after aortic occlusion. Unfortunately, all patients re-arrested soon after intra-aortic balloon deflation and none survived to hospital admission. At 30 seconds post-aortic occlusion, investigators noted a statistically significant increase in end tidal carbon dioxide of 26% (95% confidence interval, 10%, 44%). Conclusion: Initiating REBOA for OHCA patients in an academic urban ED setting is feasible. Aortic occlusion during chest compressions is temporally associated with improvements in end tidal carbon dioxide 30 seconds after aortic occlusion. Four of 5 patients achieved ROSC after aortic occlusion; however, deflation of the intra-aortic balloon quickly led to re-arrest and death in all patients. Future research should focus on the utilization of partial-REBOA to prevent re-arrest after ROSC, as well as the optimal way to incorporate this technique with other endovascular reperfusion strategies.

Bedside monitoring of hypoxic ischemic brain injury using low-field, portable brain magnetic resonance imaging after cardiac arrest.

BACKGROUND: Assessment of brain injury severity is critically important after survival from cardiac arrest (CA). Recent advances in low-field MRI technology have permitted the acquisition of clinically useful bedside brain imaging. Our objective was to deploy a novel approach for evaluating brain injury after CA in critically ill patients at high risk for adverse neurological outcome. METHODS: This retrospective, single center study involved review of all consecutive portable MRIs performed as part of clinical care for CA patients between September 2020 and January 2022. Portable MR images were retrospectively reviewed by a blinded board-certified neuroradiologist (S.P.). Fluid-inversion recovery (FLAIR) signal intensities were measured in select regions of interest. RESULTS: We performed 22 low-field MRI examinations in 19 patients resuscitated from CA (68.4% male, mean [standard deviation] age, 51.8 [13.1] years). Twelve patients (63.2%) had findings consistent with HIBI on conventional neuroimaging radiology report. Low-field MRI detected findings consistent with HIBI in all of these patients. Low-field MRI was acquired at a median (interquartile range) of 78 (40-136) hours post-arrest. Quantitatively, we measured FLAIR signal intensity in three regions of interest, which were higher amongst patients with confirmed HIBI. Low-field MRI was completed in all patients without disruption of intensive care unit equipment monitoring and no safety events occurred. CONCLUSION: In a critically ill CA population in whom MR imaging is often not feasible, low-field MRI can be deployed at the bedside to identify HIBI. Low-field MRI provides an opportunity to evaluate the time-dependent nature of MRI findings in CA survivors.

Portable, low-field magnetic resonance imaging enables highly accessible and dynamic bedside evaluation of ischemic stroke.

Brain imaging is essential to the clinical management of patients with ischemic stroke. Timely and accessible neuroimaging, however, can be limited in clinical stroke pathways. Here, portable magnetic resonance imaging (pMRI) acquired at very low magnetic field strength (0.064 T) is used to obtain actionable bedside neuroimaging for 50 confirmed patients with ischemic stroke. Low-field pMRI detected infarcts in 45 (90%) patients across cortical, subcortical, and cerebellar structures. Lesions as small as 4 mm were captured. Infarcts appeared as hyperintense regions on T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted imaging sequences. Stroke volume measurements were consistent across pMRI sequences and between low-field pMRI and conventional high-field MRI studies. Low-field pMRI stroke volumes significantly correlated with stroke severity and functional outcome at discharge. These results validate the use of low-field pMRI to obtain clinically useful imaging of stroke, setting the stage for use in resource-limited environments.

Outcomes of Endovascular Therapy in Patients With Prestroke Mobility Impairment.

Background and Purpose: Patients with prestroke mobility impairment (PSMI) were excluded from endovascular clinical trials. There are limited data regarding safety and outcomes of endovascular thrombectomy in this population. We used a large, national data set (Get With The Guidelines­Stroke) to evaluate the safety and outcomes of endovascular thrombectomy in patients with PSMI. Methods: We included patients who underwent endovascular thrombectomy in the Get With The Guidelines­Stroke registry between 2015 and 2019. PSMI was defined as the inability to ambulate independently. Generalized estimating equations for logistic regression models were used to evaluate the association between PSMI and outcomes. Results: Of 56 762 patients treated with endovascular thrombectomy, 2919 (5.14%) had PSMI. PSMI was not associated with symptomatic intracranial hemorrhage (6.0% versus 5.4%; P=0.979). In-hospital death or discharge to hospice occurred in 32.3% of patients with PSMI versus 17.5% without PSMI (adjusted odds ratio, 1.45 [1.32­1.58]). Conclusions: While procedural adverse outcomes were no higher in patients with PSMI, further study is necessary to determine clinical benefit in this population.

Portable, bedside, low-field magnetic resonance imaging for evaluation of intracerebral hemorrhage.

Radiological examination of the brain is a critical determinant of stroke care pathways. Accessible neuroimaging is essential to detect the presence of intracerebral hemorrhage (ICH). Conventional magnetic resonance imaging (MRI) operates at high magnetic field strength (1.5-3 T), which requires an access-controlled environment, rendering MRI often inaccessible. We demonstrate the use of a low-field MRI (0.064 T) for ICH evaluation. Patients were imaged using conventional neuroimaging (non-contrast computerized tomography (CT) or 1.5/3 T MRI) and portable MRI (pMRI) at Yale New Haven Hospital from July 2018 to November 2020. Two board-certified neuroradiologists evaluated a total of 144 pMRI examinations (56 ICH, 48 acute ischemic stroke, 40 healthy controls) and one ICH imaging core lab researcher reviewed the cases of disagreement. Raters correctly detected ICH in 45 of 56 cases (80.4% sensitivity, 95%CI: [0.68-0.90]). Blood-negative cases were correctly identified in 85 of 88 cases (96.6% specificity, 95%CI: [0.90-0.99]). Manually segmented hematoma volumes and ABC/2 estimated volumes on pMRI correlate with conventional imaging volumes (ICC = 0.955, p = 1.69e-30 and ICC = 0.875, p = 1.66e-8, respectively). Hematoma volumes measured on pMRI correlate with NIH stroke scale (NIHSS) and clinical outcome (mRS) at discharge for manual and ABC/2 volumes. Low-field pMRI may be useful in bringing advanced MRI technology to resource-limited settings.