Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion: In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov (NCT04217551, 2019-12-30).

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Improving Outcomes After Post-Cardiac Arrest Brain Injury: A Scientific Statement From the International Liaison Committee on Resuscitation.

This scientific statement presents a conceptual framework for the pathophysiology of post-cardiac arrest brain injury, explores reasons for previous failure to translate preclinical data to clinical practice, and outlines potential paths forward. Post-cardiac arrest brain injury is characterized by 4 distinct but overlapping phases: ischemic depolarization, reperfusion repolarization, dysregulation, and recovery and repair. Previous research has been challenging because of the limitations of laboratory models; heterogeneity in the patient populations enrolled; overoptimistic estimation of treatment effects leading to suboptimal sample sizes; timing and route of intervention delivery; limited or absent evidence that the intervention has engaged the mechanistic target; and heterogeneity in postresuscitation care, prognostication, and withdrawal of life-sustaining treatments. Future trials must tailor their interventions to the subset of patients most likely to benefit and deliver this intervention at the appropriate time, through the appropriate route, and at the appropriate dose. The complexity of post-cardiac arrest brain injury suggests that monotherapies are unlikely to be as successful as multimodal neuroprotective therapies. Biomarkers should be developed to identify patients with the targeted mechanism of injury, to quantify its severity, and to measure the response to therapy. Studies need to be adequately powered to detect effect sizes that are realistic and meaningful to patients, their families, and clinicians. Study designs should be optimized to accelerate the evaluation of the most promising interventions. Multidisciplinary and international collaboration will be essential to realize the goal of developing effective therapies for post-cardiac arrest brain injury.

Improving Outcomes After Post-Cardiac Arrest Brain Injury: A Scientific Statement From the International Liaison Committee on Resuscitation.

This scientific statement presents a conceptual framework for the pathophysiology of post-cardiac arrest brain injury, explores reasons for previous failure to translate preclinical data to clinical practice, and outlines potential paths forward. Post-cardiac arrest brain injury is characterized by 4 distinct but overlapping phases: ischemic depolarization, reperfusion repolarization, dysregulation, and recovery and repair. Previous research has been challenging because of the limitations of laboratory models; heterogeneity in the patient populations enrolled; overoptimistic estimation of treatment effects leading to suboptimal sample sizes; timing and route of intervention delivery; limited or absent evidence that the intervention has engaged the mechanistic target; and heterogeneity in postresuscitation care, prognostication, and withdrawal of life-sustaining treatments. Future trials must tailor their interventions to the subset of patients most likely to benefit and deliver this intervention at the appropriate time, through the appropriate route, and at the appropriate dose. The complexity of post-cardiac arrest brain injury suggests that monotherapies are unlikely to be as successful as multimodal neuroprotective therapies. Biomarkers should be developed to identify patients with the targeted mechanism of injury, to quantify its severity, and to measure the response to therapy. Studies need to be adequately powered to detect effect sizes that are realistic and meaningful to patients, their families, and clinicians. Study designs should be optimized to accelerate the evaluation of the most promising interventions. Multidisciplinary and international collaboration will be essential to realize the goal of developing effective therapies for post-cardiac arrest brain injury.

Engagement in mHealth-Prompted Self-Measured Blood Pressure Monitoring Among Participants Recruited From a Safety-Net Emergency Department: Secondary Analysis of the Reach Out Trial.

Background: Hypertension, a key modifiable risk factor for cardiovascular disease, is more prevalent among Black and low-income individuals. To address this health disparity, leveraging safety-net emergency departments for scalable mobile health (mHealth) interventions, specifically using text messaging for self-measured blood pressure (SMBP) monitoring, presents a promising strategy. This study investigates patterns of engagement, associated factors, and the impact of engagement on lowering blood pressure (BP) in an underserved population. Objective: We aimed to identify patterns of engagement with prompted SMBP monitoring with feedback, factors associated with engagement, and the association of engagement with lowered BP. Methods: This is a secondary analysis of data from Reach Out, an mHealth, factorial trial among 488 hypertensive patients recruited from a safety-net emergency department in Flint, Michigan. Reach Out participants were randomized to weekly or daily text message prompts to measure their BP and text in their responses. Engagement was defined as a BP response to the prompt. The k-means clustering algorithm and visualization were used to determine the pattern of SMBP engagement by SMBP prompt frequency-weekly or daily. BP was remotely measured at 12 months. For each prompt frequency group, logistic regression models were used to assess the univariate association of demographics, access to care, and comorbidities with high engagement. We then used linear mixed-effects models to explore the association between engagement and systolic BP at 12 months, estimated using average marginal effects. Results: For both SMBP prompt groups, the optimal number of engagement clusters was 2, which we defined as high and low engagement. Of the 241 weekly participants, 189 (78.4%) were low (response rate: mean 20%, SD 23.4) engagers, and 52 (21.6%) were high (response rate: mean 86%, SD 14.7) engagers. Of the 247 daily participants, 221 (89.5%) were low engagers (response rate: mean 9%, SD 12.2), and 26 (10.5%) were high (response rate: mean 67%, SD 8.7) engagers. Among weekly participants, those who were older (>65 years of age), attended some college (vs no college), married or lived with someone, had Medicare (vs Medicaid), were under the care of a primary care doctor, and took antihypertensive medication in the last 6 months had higher odds of high engagement. Participants who lacked transportation to appointments had lower odds of high engagement. In both prompt frequency groups, participants who were high engagers had a greater decline in BP compared to low engagers. Conclusions: Participants randomized to weekly SMBP monitoring prompts responded more frequently overall and were more likely to be classed as high engagers compared to participants who received daily prompts. High engagement was associated with a larger decrease in BP. New strategies to encourage engagement are needed for participants with lower access to care.

Exploring the Acceptability and Feasibility of Remote Blood Pressure Measurements and Cognition Assessments Among Participants Recruited From a Safety-Net Emergency Department (Reach Out Cognition): Nonrandomized Mobile Health Trial.

BACKGROUND: Hypertension is a prevalent cardiovascular risk factor disproportionately affecting Black Americans, who also experience a higher incidence of Alzheimer disease and Alzheimer disease-related dementias. Monitoring blood pressure (BP) and cognition may be important strategies in reducing these disparities. OBJECTIVE: The objective of the Reach Out Cognition study was to explore the feasibility and acceptability of remote cognitive and BP assessments in a predominantly Black, low-income population. METHODS: Reach Out was a randomized, controlled, mobile health-based clinical trial to reduce BP among patients with hypertension at an emergency department in a safety-net hospital (ie, a US hospital in which 25% of the patients are Medicaid recipients). Upon conclusion of Reach Out, participants were given the option of continuing into an extension phase, Reach Out Cognition, that included Bluetooth-enabled BP monitoring and digital cognitive assessments for 6 months. Digital cognitive assessments were text message-linked online surveys of the Self-Administered Gerocognitive Exam and Quality of Life in Neurological Disorders scale. BP assessments were measured with Bluetooth-enabled BP cuffs paired with an app and the data were manually sent to the research team. Outcomes were feasibility (ie, enrollment and 3- and 6-month completion of digital cognitive and BP assessments) and acceptability of assessments using a 4-item validated survey, ranging from 1 (not acceptable) to 5 (completely acceptable). RESULTS: Of the 211 Reach Out participants, 107 (50.7%) consented and 71 (33.6%) completed enrollment in Reach Out Cognition. Participants had a mean age of 49.9 years; 70.4% were female and 57.8% identified as Black. Among the 71 participants, 51 (72%) completed cognitive assessments at 3 months and 34 (48%) completed these assessments at 6 months. BP assessments were completed by 37 (52%) and 20 (28%) of the 71 participants at 3 and 6 months, respectively. Participants were neutral on the acceptability of the digital cognitive assessments (mean 3.7) and Bluetooth self-measured BP (SMBP) monitoring (mean 3.9). Participants noted challenges syncing the BP cuff to the app, internet connection, and transmitting the data to the research team. CONCLUSIONS: Enrollment and assessment completion were low, while acceptability was moderate. Technological advances will eliminate some of the Bluetooth SMBP barriers and offer new strategies for cognitive assessments. Subsequent studies could benefit from offering more comprehensive support to overcome Bluetooth-related hurdles, such as personalized training materials, video conferencing, or in-person research team support. Alternatively, strategies that do not require pairing with an app and passive transmission of data could be considered. Overall, further research is warranted to optimize participant engagement and overcome technological challenges. TRIAL REGISTRATION: ClinicalTrials.gov NCT03422718; https://clinicaltrials.gov/study/NCT03422718.

High-Flow Nasal Cannula Versus Noninvasive Ventilation as Initial Treatment in Acute Hypoxia: A Propensity Score-Matched Study.

IMPORTANCE: Patients presenting to the emergency department (ED) with hypoxemia often have mixed or uncertain causes of respiratory failure. The optimal treatment for such patients is unclear. Both high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) are used. OBJECTIVES: We sought to compare the effectiveness of initial treatment with HFNC versus NIV for acute hypoxemic respiratory failure. DESIGN SETTING AND PARTICIPANTS: We conducted a retrospective cohort study of patients with acute hypoxemic respiratory failure treated with HFNC or NIV within 24 hours of arrival to the University of Michigan adult ED from January 2018 to December 2022. We matched patients 1:1 using a propensity score for odds of receiving NIV. MAIN OUTCOMES AND MEASURES: The primary outcome was major adverse pulmonary events (28-d mortality, ventilator-free days, noninvasive respiratory support hours) calculated using a win ratio. RESULTS: A total of 1154 patients were included. Seven hundred twenty-six (62.9%) received HFNC and 428 (37.1%) received NIV. We propensity score matched 668 of 1154 (57.9%) patients. Patients on NIV versus HFNC had lower 28-day mortality (16.5% vs. 23.4%, p = 0.033) and required noninvasive treatment for fewer hours (median 7.5 vs. 13.5, p < 0.001), but had no difference in ventilator-free days (median [interquartile range]: 28 [26, 28] vs. 28 [10.5, 28], p = 0.199). Win ratio for composite major adverse pulmonary events favored NIV (1.38; 95% CI, 1.15-1.65; p < 0.001). CONCLUSIONS AND RELEVANCE: In this observational study of patients with acute hypoxemic respiratory failure, initial treatment with NIV compared with HFNC was associated with lower mortality and fewer composite major pulmonary adverse events calculated using a win ratio. These findings underscore the need for randomized controlled trials to further understand the impact of noninvasive respiratory support strategies.

Clinicians' approach to predicting post-cardiac arrest outcomes for patients enrolled in a United States clinical trial.

PURPOSE: Perceived poor prognosis can lead to withdrawal of life-sustaining therapies (WLST) in patients who might otherwise recover. We characterized clinicians' approach to post-arrest prognostication in a multicenter clinical trial. METHODS: Semi-structured interviews were conducted with clinicians who treated a comatose post-cardiac arrest patient enrolled in the Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients (ICECAP) trial (NCT04217551). Two authors independently analyzed each interview using inductive and deductive coding. The clinician reported how they arrived at a prognosis for the specific patient. We summarized the frequency with which clinicians reported using objective diagnostics to formulate their prognosis, and compared the reported approaches to established guidelines. Each respondent provided demographic information and described local neuroprognostication practices. RESULTS: We interviewed 30 clinicians at 19 US hospitals. Most claimed adherence to local hospital neuroprognostication protocols (n = 19). Prognostication led to WLST for perceived poor neurological prognosis in 15/30 patients, of whom most showed inconsistencies with guidelines or trial recommendations, respectively. In 10/15 WLST cases, clinicians reported relying on multimodal testing. A prevalent theme was the use of "clinical gestalt," defined as prognosticating based on a patient's overall appearance or a subjective impression in the absence of objective data. Many clinicians (21/30) reported using clinical gestalt for initial prognostication, with 9/21 expressing high confidence initially. CONCLUSION: Clinicians in our study state they follow neuroprognostication guidelines in general but often do not do so in actual practice. They reported clinical gestalt frequently informed early, highly confident prognostic judgments, and few objective tests changed initial impressions. Subjective prognostication may undermine well-designed trials.

High-flow nasal cannula vs non-invasive ventilation in acute hypoxia: Propensity score matched study.

RATIONALE: The optimal treatment for early hypoxemic respiratory failure is unclear, and both high-flow nasal cannula and non-invasive ventilation are used. Determining clinically relevant outcomes for evaluating non-invasive respiratory support modalities remains a challenge. OBJECTIVES: To compare the effectiveness of initial treatment with high-flow nasal cannula versus non-invasive ventilation for acute hypoxemic respiratory failure. METHODS: We conducted a retrospective cohort study of patients with acute hypoxemic respiratory failure treated with high-flow nasal cannula or non-invasive ventilation within 24 hours of Emergency Department arrival (1/2018-12/2022). We matched patients 1:1 using a propensity score for odds of receiving non-invasive ventilation. The primary outcome was major adverse pulmonary events (28-day mortality, ventilator-free days, non-invasive respiratory support hours) calculated using a Win Ratio. MEASUREMENTS AND MAIN RESULTS: 1,265 patients met inclusion criteria. 795 (62.8%) received high-flow oxygen and 470 (37.2%) received non-invasive ventilation. We propensity score matched 736/1,265 (58.2%) patients. There was no difference between non-invasive ventilation vs high-flow nasal cannula in 28-day mortality (17.7% vs 23.1%, p=0.08) or ventilator-free days (median [Interquartile Range]: 28 [25, 28] vs 28 [13, 28], p=0.50), but patients on non-invasive ventilation required treatment for fewer hours (median 7 vs 13, p< 0.001). Win Ratio for composite major adverse pulmonary events favored non-invasive ventilation (1.26, 95%CI 1.06-1.49, p< 0.001). CONCLUSIONS: In this observational study of patients with acute hypoxemic respiratory failure, initial treatment with non-invasive ventilation was superior to high-flow nasal cannula for major pulmonary adverse events. Evaluation of composite outcomes is important in the assessment of respiratory support modalities.

Association of the Stroke Ready Community-Based Participatory Research Intervention With Incidence of Acute Stroke Thrombolysis in Flint, Michigan.

Importance: Acute stroke treatment rates in the US lag behind those in other high-income nations. Objective: To assess whether a hospital emergency department (ED) and community intervention was associated with an increased proportion of patients with stroke receiving thrombolysis. Design, Setting, and Participants: This nonrandomized controlled trial of the Stroke Ready intervention took place in Flint, Michigan, from October 2017 to March 2020. Participants included adults living in the community. Data analysis was completed from July 2022 to May 2023. Intervention: Stroke Ready combined implementation science and community-based participatory research approaches. Acute stroke care was optimized in a safety-net ED, and then a community-wide, theory-based health behavior intervention, including peer-led workshops, mailers, and social media, was conducted. Main Outcomes and Measures: The prespecified primary outcome was the proportion of patients hospitalized with ischemic stroke or transient ischemic attack from Flint who received thrombolysis before and after the intervention. The association between thrombolysis and the Stroke Ready combined intervention, including the ED and community components, was estimated using logistic regression models, clustering at the hospital level and adjusting for time and stroke type. In prespecified secondary analyses, the ED and community intervention were explored separately, adjusting for hospital, time, and stroke type. Results: In total, 5970 people received in-person stroke preparedness workshops, corresponding to 9.7% of the adult population in Flint. There were 3327 ischemic stroke and TIA visits (1848 women [55.6%]; 1747 Black individuals [52.5%]; mean [SD] age, 67.8 [14.5] years) among patients from Flint seen in the relevant EDs, including 2305 in the preintervention period from July 2010 to September 2017 and 1022 in the postintervention period from October 2017 to March 2020. The proportion of thrombolysis usage increased from 4% in 2010 to 14% in 2020. The combined Stroke Ready intervention was not associated with thrombolysis use (adjusted odds ratio [OR], 1.13; 95% CI, 0.74-1.70; P = .58). The ED component was associated with an increase in thrombolysis use (adjusted OR, 1.63; 95% CI, 1.04-2.56; P = .03), but the community component was not (adjusted OR, 0.99; 95% CI, 0.96-1.01; P = .30). Conclusions and Relevance: This nonrandomized controlled trial found that a multilevel ED and community stroke preparedness intervention was not associated with increased thrombolysis treatments. The ED intervention was associated with increased thrombolysis usage, suggesting that implementation strategies in partnership with safety-net hospitals may increase thrombolysis usage. Trial Registration: ClinicalTrials.gov Identifier: NCT036455900.

Effect of propranolol and clonidine after severe traumatic brain injury: a pilot randomized clinical trial.

OBJECTIVE: To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). BACKGROUND: Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit. METHODS: This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16-64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study. RESULTS: Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (- 5.4, 5.8), p = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p = 0.012), there were no between-group differences in the secondary outcomes. CONCLUSION: Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048.

Reach Out Emergency Department: A Randomized Factorial Trial to Determine the Optimal Mobile Health Components to Reduce Blood Pressure.

BACKGROUND: Mobile health (mHealth) strategies initiated in safety-net Emergency Departments may be one approach to address the US hypertension epidemic, but the optimal mHealth components or dose are unknown. METHODS: Reach Out is an mHealth, health theory-based, 2×2×2 factorial trial among hypertensive patients evaluated in a safety-net Emergency Department in Flint, Michigan. Reach Out consisted of 3 mHealth components, each with 2 doses: (1) healthy behavior text messaging (yes versus no), (2) prompted self-measured blood pressure (BP) monitoring and feedback (weekly versus daily), and (3) facilitated primary care provider appointment scheduling and transportation (yes versus no). The primary outcome was a change in systolic BP from baseline to 12 months. In a complete case analysis, we fit a linear regression model and accounted for age, sex, race, and prior BP medications to explore the association between systolic BP and each mHealth component. RESULTS: Among 488 randomized participants, 211 (43%) completed follow-up. Mean age was 45.5 years, 61% were women, 54% were Black people, 22% did not have a primary care doctor, 21% lacked transportation, and 51% were not taking antihypertensive medications. Overall, systolic BP declined after 6 months (-9.2 mm Hg [95% CI, -12.2 to -6.3]) and 12 months (-6.6 mm Hg, -9.3 to -3.8), without a difference across the 8 treatment arms. The higher dose of mHealth components were not associated with a greater change in systolic BP; healthy behavior text messages (point estimate, mmHG=-0.5 [95% CI, -6.0 to 5]; P=0.86), daily self-measured BP monitoring (point estimate, mmHG=1.9 [95% CI, -3.7 to 7.5]; P=0.50), and facilitated primary care provider scheduling and transportation (point estimate, mmHG=0 [95% CI, -5.5 to 5.6]; P=0.99). CONCLUSIONS: Among participants with elevated BP recruited from an urban safety-net Emergency Department, BP declined over the 12-month intervention period. There was no difference in change in systolic BP among the 3 mHealth components. Reach Out demonstrated the feasibility of reaching medically underserved people with high BP cared for at a safety-net Emergency Departments, yet the efficacy of the Reach Out mHealth intervention components requires further study. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03422718.

Guidelines for reasonable and appropriate care in the emergency department 3 (GRACE-3): Acute dizziness and vertigo in the emergency department.

This third Guideline for Reasonable and Appropriate Care in the Emergency Department (GRACE-3) from the Society for Academic Emergency Medicine is on the topic adult patients with acute dizziness and vertigo in the emergency department (ED). A multidisciplinary guideline panel applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding five questions for adult ED patients with acute dizziness of less than 2 weeks' duration. The intended population is adults presenting to the ED with acute dizziness or vertigo. The panel derived 15 evidence-based recommendations based on the timing and triggers of the dizziness but recognizes that alternative diagnostic approaches exist, such as the STANDING protocol and nystagmus examination in combination with gait unsteadiness or the presence of vascular risk factors. As an overarching recommendation, (1) emergency clinicians should receive training in bedside physical examination techniques for patients with the acute vestibular syndrome (AVS; HINTS) and the diagnostic and therapeutic maneuvers for benign paroxysmal positional vertigo (BPPV; Dix-Hallpike test and Epley maneuver). To help distinguish central from peripheral causes in patients with the AVS, we recommend: (2) use HINTS (for clinicians trained in its use) in patients with nystagmus, (3) use finger rub to further aid in excluding stroke in patients with nystagmus, (4) use severity of gait unsteadiness in patients without nystagmus, (5) do not use brain computed tomography (CT), (6) do not use routine magnetic resonance imaging (MRI) as a first-line test if a clinician trained in HINTS is available, and (7) use MRI as a confirmatory test in patients with central or equivocal HINTS examinations. In patients with the spontaneous episodic vestibular syndrome: (8) search for symptoms or signs of cerebral ischemia, (9) do not use CT, and (10) use CT angiography or MRI angiography if there is concern for transient ischemic attack. In patients with the triggered (positional) episodic vestibular syndrome, (11) use the Dix-Hallpike test to diagnose posterior canal BPPV (pc-BPPV), (12) do not use CT, and (13) do not use MRI routinely, unless atypical clinical features are present. In patients diagnosed with vestibular neuritis, (14) consider short-term steroids as a treatment option. In patients diagnosed with pc-BPPV, (15) treat with the Epley maneuver. It is clear that as of 2023, when applied in routine practice by emergency clinicians without special training, HINTS testing is inaccurate, partly due to use in the wrong patients and partly due to issues with its interpretation. Most emergency physicians have not received training in use of HINTS. As such, it is not standard of care, either in the legal sense of that term ("what the average physician would do in similar circumstances") or in the common parlance sense ("the standard action typically used by physicians in routine practice").

Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke: A Randomized Clinical Trial.

Importance: Dual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone because mutant prourokinase is designed to act only on degraded fibrin without affecting circulating fibrinogen. Objective: To assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase. Design, Setting, and Participants: This controlled, open-label randomized clinical trial with a blinded end point was conducted from August 10, 2019, to March 26, 2022, with a total follow-up of 30 days. Adult patients with ischemic stroke from 4 stroke centers in the Netherlands were enrolled. Interventions: Patients were randomized (1:1) to receive a bolus of 5 mg of intravenous alteplase and 40 mg of an intravenous infusion of mutant prourokinase (intervention) or usual care with 0.9 mg/kg of intravenous alteplase (control). Main Outcomes and Measures: The primary outcome was any intracranial hemorrhage (ICH) on neuroimaging at 24 hours. Secondary outcomes included functional outcome at 30 days, symptomatic ICH, and fibrinogen levels within 24 hours. Analyses were by intention to treat. Treatment effects were adjusted for baseline prognostic factors. Results: A total of 268 patients were randomized, and 238 (median [IQR] age, 69 [59-77] years; 147 [61.8%] male) provided deferred consent and were included in the intention-to-treat population (121 in the intervention group and 117 in the control group). The median baseline score on the National Institutes of Health Stroke Scale was 3 (IQR, 2-5). Any ICH occurred in 16 of 121 patients (13.2%) in the intervention group and 16 of 117 patients (13.7%) in the control group (adjusted odds ratio, 0.98; 95% CI, 0.46-2.12). Mutant prourokinase led to a nonsignificant shift toward better modified Rankin Scale scores (adjusted common odds ratio, 1.16; 95% CI, 0.74-1.84). Symptomatic ICH occurred in none of the patients in the intervention group and 3 of 117 patients (2.6%) in the control group. Plasma fibrinogen levels at 1 hour remained constant in the intervention group but decreased in the control group (ß = 65 mg/dL; 95% CI, 26-105 mg/dL). Conclusions and Relevance: In this trial, dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was found to be safe and did not result in fibrinogen depletion. Further evaluation of thrombolytic treatment with mutant prourokinase in larger trials to improve outcomes in patients with larger ischemic strokes is needed. Overall, in patients with minor ischemic stroke who met indications for treatment with intravenous thrombolytics but were not eligible for treatment with endovascular therapy, dual thrombolytic therapy with intravenous mutant prourokinase was not superior to treatment with intravenous alteplase alone. Trial Registration: ClinicalTrials.gov Identifier: NCT04256473.

Recurrent stroke arrival time.

BACKGROUND: Stroke patients and family members should receive stroke education including recognition of stroke symptoms and prompt activation of emergency medical services (EMS). The impact of this education is unclear. We aimed to measure the associations between EMS use and timing of hospital arrival and first-ever and recurrent strokes as a proxy for stroke education. METHODS: The study analyzed data from validated strokes identified by the Brain Attack Surveillance in Corpus Christi (BASIC) project between 1/1/2000-1/1/2020. We analyzed 5,617 first-ever strokes, 259 instances of recurrent stroke within 1 year of the first (early recurrence), and 451 recurrent strokes over 1 year from the first (late recurrence). Following imputation, associations of both EMS arrival (available starting late 2011) and early arrival (< 3 hours) with first-ever versus recurrent stroke (early and late) were assessed with logistic models, accounting for the clustering of multiple strokes per participant with generalized estimating equations. Full model covariates included stroke type, initial stroke severity, marital status, race/ethnicity, gender, age, insurance, education, and EMS use (early arrival model only). RESULTS: Compared to first-ever stroke, there were significantly higher unadjusted odds of arrival by EMS for the late recurrence group (late recurrence OR = 1.54, 95% CI = 1.18-1.99; early arrival OR = 1.24, 95% CI = 0.87-1.76). The association for late recurrence remained significant after adjustment (aOR = 1.46, 95% CI = 1.09-1.95). The pre-2010 unadjusted odds of early arrival were non-significant for both early and late recurrence groups (late recurrence OR = 1.05, CI = 0.70-1.56; early recurrence OR = 0.85, CI = 0.54-1.33), while late recurrence was associated with early arrival after 2010 (OR = 1.32, 95% CI = 1.03-1.69). After full adjustment, it was no longer significant (aOR = 1.25, 95% CI = 0.96-1.62). Higher initial stroke severity, married status, and EMS use were associated with higher odds of early arrival, while African Americans (AAs) had lower odds than non-Hispanic Whites (NHWs). However, AAs did have higher odds of EMS use relative to NHWs. Those who were married and living together had borderline significant lower odds of EMS use compared to those who were not. CONCLUSIONS: Our study examines the association of repeat stroke on early arrival and EMS use as a surrogate for adequate stroke education. Recurrence at least one year after the first stroke was associated with higher EMS usage, but there was not enough evidence to establish a relationship with early arrival after accounting for EMS usage and possible confounders. By examining subsets, we can identify groups that would benefit from targeted education. For example, younger, non-AA patients with smaller strokes would benefit from more education on EMS use and African American patients would benefit from education related to faster recognition or urgency of presentation.

Engagement in Self-measured Blood Pressure Monitoring Among Medically Underresourced Participants (the Reach Out Trial): Digital Framework Qualitative Study.

BACKGROUND: Mobile health (mHealth) interventions serve as a scalable opportunity to engage people with hypertension in self-measured blood pressure (SMBP) monitoring, an evidence-based approach to lowering blood pressure (BP) and improving BP control. Reach Out is an SMS text messaging-based SMBP mHealth trial that aims to reduce BP among hypertensive patients recruited from the emergency department of a safety net hospital in a low-income, predominately Black city. OBJECTIVE: As the benefits of Reach Out are predicated on participants' engagement with the intervention, we sought to understand participants' determinants of engagement via prompted SMBP with personalized feedback (SMBP+feedback). METHODS: We conducted semistructured telephone interviews based on the digital behavior change interventions framework. Participants were purposively sampled from 3 engagement categories: high engagers (≥80% response to SMBP prompts), low engagers (≤20% response to BP prompts), and early enders (participants who withdrew from the trial). RESULTS: We conducted interviews with 13 participants, of whom 7 (54%) were Black, with a mean age of 53.6 (SD 13.25) years. Early enders were less likely to be diagnosed with hypertension prior to Reach Out, less likely to have a primary care provider, and less likely to be taking antihypertensive medications than their counterparts. Overall, participants liked the SMS text messaging design of the intervention, including the SMBP+feedback. Several participants across all levels of engagement expressed interest in and identified the benefit of enrolling in the intervention with a partner of their choice. High engagers expressed the greatest understanding of the intervention, the least number of health-related social needs, and the greatest social support to engage in SMBP. Low engagers and early enders shared a mixed understanding of the intervention and less social support compared to high engagers. Participation decreased as social needs increased, with early enders sharing the greatest amount of resource insecurity apart from a notable exception of a high engager with high health-related social needs. CONCLUSIONS: Prompted SMBP+feedback was perceived favorably by all participants. To enhance SMBP engagement, future studies could consider greater support in the initiation of SMBP, evaluating and addressing participants' unmet health-related social needs, as well as strategies to cultivate social norms.

Clinical Performance Measures for Emergency Department Care for Adults With Intracranial Hemorrhage.

Though select inpatient-based performance measures exist for the care of patients with nontraumatic intracranial hemorrhage, emergency departments lack measurement instruments designed to support and improve care processes in the hyperacute phase. To address this, we propose a set of measures applying a syndromic (rather than diagnosis-based) approach informed by performance data from a national sample of community EDs participating in the Emergency Quality Network Stroke Initiative. To develop the measure set, we convened a workgroup of experts in acute neurologic emergencies. The group considered the appropriate use case for each proposed measure: internal quality improvement, benchmarking, or accountability, and examined data from Emergency Quality Network Stroke Initiative-participating EDs to consider the validity and feasibility of proposed measures for quality measurement and improvement applications. The initially conceived set included 14 measure concepts, of which 7 were selected for inclusion in the measure set after a review of data and further deliberation. Proposed measures include 2 for quality improvement, benchmarking, and accountability (Last 2 Recorded Systolic Blood Pressure Measurements Under 150 and Platelet Avoidance), 3 for quality improvement and benchmarking (Proportion of Patients on Oral Anticoagulants Receiving Hemostatic Medications, Median ED Length of Stay for admitted patients, and Median Length of Stay for transferred patients), and 2 for quality improvement only (Severity Assessment in the ED and Computed Tomography Angiography Performance). The proposed measure set warrants further development and validation to support broader implementation and advance national health care quality goals. Ultimately, applying these measures may help identify opportunities for improvement and focus quality improvement resources on evidence-based targets.