Faculty Bibliography

BACKGROUND:Limited data exist regarding the optimal clinical trial design for studies involving persons with disorders of consciousness (DoC), and only a few therapies have been tested in high-quality clinical trials. To address this, the Curing Coma Campaign Clinical Trial Working Group performed a gap analysis on the current state of clinical trials in DoC to identify the optimal clinical design for studies involving persons with DoC. METHODS:The Curing Coma Campaign Clinical Trial Working Group was divided into three subgroups to (1) review clinical trials involving persons with DoC, (2) identify unique challenges in the design of clinical trials involving persons with DoC, and (3) recommend optimal clinical trial designs for DoC. RESULTS:There were 3055 studies screened, and 66 were included in this review. Several knowledge gaps and unique challenges were identified. There is a lack of high-quality clinical trials, and most data regarding patients with DoC are based on observational studies focusing on patients with traumatic brain injury and cardiac arrest. There is a lack of a structured long-term outcome assessment with significant heterogeneity in the methodology, definitions of outcomes, and conduct of studies, especially for long-term follow-up. Another major barrier to conducting clinical trials is the lack of resources, especially in low-income countries. Based on the available data, we recommend incorporating trial designs that use master protocols, sequential multiple assessment randomized trials, and comparative effectiveness research. Adaptive platform trials using a multiarm, multistage approach offer substantial advantages and should make use of biomarkers to assess treatment responses to increase trial efficiency. Finally, sound infrastructure and international collaboration are essential to facilitate the conduct of trials in patients with DoC. CONCLUSIONS:Conduct of trials in patients with DoC should make use of master protocols and adaptive design and establish international registries incorporating standardized assessment tools. This will allow the establishment of evidence-based practice recommendations and decrease variations in care.

OBJECTIVE/UNASSIGNED:A significant number of patients develop anxiety after stroke. The objective of this study was to identify risk factors for anxiety after hemorrhagic stroke that may facilitate diagnosis and treatment. METHODS/UNASSIGNED:Patients admitted between January 2015 and February 2021 with nontraumatic hemorrhagic stroke (intracerebral [ICH] or subarachnoid [SAH] hemorrhage) were assessed telephonically 3 and 12 months after stroke with the Quality of Life in Neurological Disorders Anxiety Short Form to evaluate the relationships between poststroke anxiety (T score >50) and preclinical social and neuropsychiatric history, systemic and neurological illness severity, and in-hospital complications. RESULTS/UNASSIGNED:Of 71 patients who completed the 3-month assessment, 28 (39%) had anxiety. There was a difference in Glasgow Coma Scale (GCS) scores on admission between patients with anxiety (median=14, interquartile range [IQR]=12-15) and those without anxiety (median=15, IQR=14-15) (p=0.034), and the incidence of anxiety was higher among patients with ICH (50%) than among those with SAH (20%) (p=0.021). Among patients with ICH, anxiety was associated with larger median ICH volume (25 cc [IQR=8-46] versus 8 cc [IQR=3-13], p=0.021) and higher median ICH score (2 [IQR=1-3] versus 1 [IQR=0-1], p=0.037). On multivariable analysis with GCS score, hemorrhage type, and neuropsychiatric history, only hemorrhage type remained significant (odds ratio=3.77, 95% CI=1.19-12.05, p=0.024). Of the 39 patients who completed the 12-month assessment, 12 (31%) had anxiety, and there was a difference in mean National Institutes of Health Stroke Scale scores between patients with (5 [IQR=3-12]) and without (2 [IQR=0-4]) anxiety (p=0.045). There was fair agreement (κ=0.38) between the presence of anxiety at 3 and 12 months. CONCLUSIONS/UNASSIGNED:Hemorrhage characteristics and factors assessed with neurological examination on admission are associated with the development of poststroke anxiety.

OBJECTIVE/UNASSIGNED:Emotional and behavioral dyscontrol (EBD), a neuropsychiatric complication of stroke, leads to patient and caregiver distress and challenges to rehabilitation. Studies of neuropsychiatric sequelae in stroke are heavily weighted toward ischemic stroke. This study was designed to compare risk of EBD following intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) and to identify risk factors for EBD following hemorrhagic stroke. METHODS/UNASSIGNED:The authors conducted a prospective cohort study of patients hospitalized for nontraumatic hemorrhagic stroke between 2015 and 2021. Patients or legally authorized representatives completed the Quality of Life in Neurological Disorders (Neuro-QOL) EBD short-form inventory 3 months after hospitalization. Univariable and multivariable analyses identified risk factors for EBD after hemorrhagic stroke. RESULTS/UNASSIGNED:The incidence of EBD was 21% (N=15 of 72 patients) at 3 months after hemorrhagic stroke. Patients with ICH were more likely to develop EBD; 93% of patients with EBD (N=14 of 15) had ICH compared with 56% of patients without EBD (N=32 of 57). The median Glasgow Coma Scale (GCS) score at hospital admission was lower among patients who developed EBD (13 vs. 15 among those without EBD). Similarly, admission scores on the National Institutes of Health Stroke Scale (NIHSS) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) were higher among patients with EBD (median NIHSS score: 7 vs. 2; median APACHE II score: 17 vs. 11). Multivariable analyses identified hemorrhage type (ICH) and poor admission GCS score as predictors of EBD 3 months after hemorrhagic stroke. CONCLUSIONS/UNASSIGNED:Patients with ICH and a low GCS score at admission are at increased risk of developing EBD 3 months after hemorrhagic stroke and may benefit from early intervention.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The purpose of this guideline is to update the 2010 American Academy of Neurology (AAN) brain death/death by neurologic criteria (BD/DNC) guideline for adults and the 2011 American Academy of Pediatrics, Child Neurology Society, and Society of Critical Care Medicine guideline for infants and children and to clarify the BD/DNC determination process by integrating guidance for adults and children into a single guideline. Updates in this guideline include guidance related to conducting the BD/DNC evaluation in the context of extracorporeal membrane oxygenation, targeted temperature management, and primary infratentorial injury. METHODS:A panel of experts from multiple medical societies developed BD/DNC recommendations. Because of the lack of high-quality evidence on the subject, a novel, evidence-informed formal consensus process was used. This process relied on the panel experts' review and detailed knowledge of the literature surrounding BD/DNC to guide the development of preliminary recommendations. Recommendations were formulated and voted on, using a modified Delphi process, according to the 2017 AAN Clinical Practice Guideline Process Manual. MAJOR RECOMMENDATIONS/CONCLUSIONS:Eighty-five recommendations were developed on the following: (1) general principles for the BD/DNC evaluation, (2) qualifications to perform BD/DNC evaluations, (3) prerequisites for BD/DNC determination, (4) components of the BD/DNC neurologic examination, (5) apnea testing as part of the BD/DNC evaluation, (6) ancillary testing as part of the BD/DNC evaluation, and (7) special considerations for BD/DNC determination.

Interest in disorders of consciousness (DoC) has grown substantially over the past decade and has illuminated the importance of improving understanding of DoC biology; care needs (use of monitoring, performance of interventions, and provision of emotional support); treatment options to promote recovery; and outcome prediction. Exploration of these topics requires awareness of numerous ethics considerations related to rights and resources. The Curing Coma Campaign Ethics Working Group used its expertise in neurocritical care, neuropalliative care, neuroethics, neuroscience, philosophy, and research to formulate an informal review of ethics considerations along the continuum of research involving persons with DoC related to the following: (1) study design; (2) comparison of risks versus benefits; (3) selection of inclusion and exclusion criteria; (4) screening, recruitment, and enrollment; (5) consent; (6) data protection; (7) disclosure of results to surrogates and/or legally authorized representatives; (8) translation of research into practice; (9) identification and management of conflicts of interest; (10) equity and resource availability; and (11) inclusion of minors with DoC in research. Awareness of these ethics considerations when planning and performing research involving persons with DoC will ensure that the participant rights are respected while maximizing the impact and meaningfulness of the research, interpretation of outcomes, and communication of results.

In collaboration with the American Academy of Pediatrics, Child Neurology Society, and Society for Critical Care Medicine, the American Academy of Neurology formulated an updated, evidence-informed consensus-based guideline for pediatric and adult brain death/death by neurologic criteria (BD/DNC) determination. In comparison with the prior guidelines, the revisions and additions in this guideline, which are summarized in this review, are intended to (1) ensure recommendations are conservative, yet practical, and emphasize circumstances in which BD/DNC determination should be delayed or deferred, so as to minimize the risk of a false-positive BD/DNC determination; and (2) provide guidance about aspects of BD/DNC determination that clinicians find challenging and/or controversial. We hope that clinicians throughout the United States will use this information to revise their hospital BD/DNC determination policies to conform to the standardized process for BD/DNC determination described in the new guideline, to ensure that every BD/DNC evaluation is consistent and accurate.

BACKGROUND:The utility of head computed tomography (CT) in predicting elevated intracranial pressure (ICP) is known to be limited in traumatic brain injury; however, few data exist in patients with spontaneous intracranial hemorrhage. METHODS:We conducted a retrospective review of prospectively collected data in patients with nontraumatic intracranial hemorrhage (subarachnoid hemorrhage [SAH] or intraparenchymal hemorrhage [IPH]) who underwent external ventricular drain (EVD) placement. Head CT scans performed immediately prior to EVD placement were quantitatively reviewed for features suggestive of elevated ICP, including temporal horn diameter, bicaudate index, basal cistern effacement, midline shift, and global cerebral edema. The modified Fisher score (mFS), intraventricular hemorrhage score, and IPH volume were also measured, as applicable. We calculated the accuracy, positive predictive value (PPV), and negative predictive value (NPV) of these radiographic features for the coprimary outcomes of elevated ICP (> 20 mm Hg) at the time of EVD placement and at any time during the hospital stay. Multivariable backward stepwise logistic regression analysis was performed to identify significant radiographic factors associated with elevated ICP. RESULTS:Of 608 patients with intracranial hemorrhages enrolled during the study time frame, 243 (40%) received an EVD and 165 (n = 107 SAH, n = 58 IPH) had a preplacement head CT scan available for rating. Elevated opening pressure and elevated ICP during hospitalization were recorded in 48 of 152 (29%) and 103 of 165 (62%), respectively. The presence of ≥ 1 radiographic feature had only 32% accuracy for identifying elevated opening pressure (PPV 30%, NPV 58%, area under the curve [AUC] 0.537, 95% asymptotic confidence interval [CI] 0.436-0.637, P = 0.466) and 59% accuracy for predicting elevated ICP during hospitalization (PPV 63%, NPV 40%, AUC 0.514, 95% asymptotic CI 0.391-0.638, P = 0.820). There was no significant association between the number of radiographic features and ICP elevation. Head CT scans without any features suggestive of elevated ICP occurred in 25 of 165 (15%) patients. However, 10 of 25 (40%) of these patients had elevated opening pressure, and 15 of 25 (60%) had elevated ICP during their hospital stay. In multivariable models, mFS (adjusted odds ratio [aOR] 1.36, 95% CI 1.10-1.68) and global cerebral edema (aOR 2.93, 95% CI 1.27-6.75) were significantly associated with elevated ICP; however, their accuracies were only 69% and 60%, respectively. All other individual radiographic features had accuracies between 38 and 58% for identifying intracranial hypertension. CONCLUSIONS:More than 50% of patients with spontaneous intracranial hemorrhage without radiographic features suggestive of elevated ICP actually had ICP > 20 mm Hg during EVD placement or their hospital stay. Morphological head CT findings were only 32% and 59% accurate in identifying elevated opening pressure and ICP elevation during hospitalization, respectively.

Use of thoracoabdominal normothermic regional perfusion (TA-NRP) during donation after circulatory death (DCD) is an important advance in organ donation. Prior to establishing TA-NRP, the brachiocephalic, left carotid, and left subclavian arteries are ligated, thereby eliminating anterograde brain blood flow via the carotid and vertebral arteries. While theoretical concerns have been voiced that TA-NRP after DCD may restore brain blood flow via collaterals, there have been no studies to confirm or refute this possibility. We evaluated brain blood flow using intraoperative transcranial Doppler (TCD) in two DCD TA-NRP cases. Pre-extubation, anterior and posterior circulation brain blood flow waveforms were present in both cases, similar to the waveforms detected in a control patient on mechanical circulatory support undergoing cardiothoracic surgery. Following declaration of death and initiation of TA-NRP, no brain blood flow was detected in either case. Additionally, there was absence of brainstem reflexes, no response to noxious stimuli and no respiratory effort. These TCD results demonstrate that DCD with TA-NRP did not restore brain blood flow.