Subject Retention in Prehospital Stroke Research Using a Telephone-Based Physician-Investigator Driven Enrollment Method.

Background and purposeSubject retention into clinical trials is vital, and prehospital enrollment may be associated with higher rates of subject withdrawal than more traditional methods of enrollment. We describe rates of subject retention in a prehospital trial of acute stroke therapy.MethodsAll subjects were enrolled into the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) phase 3 clinical trial. Paramedics screened eligible subjects and contacted the physician-investigator using a dedicated in-ambulance cellular phone. Physician-investigators obtained explicit informed consent from the subject or on-scene legally authorized representative (LAR) who reviewed and signed a consent form. Exception from informed consent (EFIC) was utilized in later stages of the study.ResultsThere were 1,700 subjects enrolled; 1,017 provided consent (60%), 662 were enrolled via LAR (39%), and 21 were enrolled via EFIC (1%). Of the 1,700 patients, 1,413 (83%) completed the 90-day visit, 265 (16%) died prior to the 90-day visit, and 22 (1.3%) withdrew from the study before completion. There were no differences in rates of withdrawal by method of study enrolment, i.e., self-consent (n = 14), 1.4%; LAR (n = 8), 1.2%; EFIC (n = 0) 0%.ConclusionThere was a high rate of retention when subjects were enrolled into prehospital stroke research using a phone-based method to obtain explicit consent

Marked Circadian Variation in Number and Type of Hyperacute Strokes During the 24 Hour Day-Night Cycle

Introduction: Circadian variations in stroke onset provide critical information for the allocation of pre-hospital and hospital resources in clinical care. Confining analysis to patients with defined onset in waking and clearly distinguished ischemic and hemorrhagic stroke subtypes, would substantial benefit our understanding of stroke etiology. Methods: We analyzed patients enrolled in the NIH FAST-MAG phase 3 trial of field-initiated neuroprotective agents in patients with hyperacute stroke within 2h of onset. Onset times were analyzed in 1h time blocks throughout the 24h day-night cycle. Patient demographic and clinical features, medical history, imaging characteristics, and stroke deficit severity were correlated with onset times. Results: Among 1632 patients, final diagnoses were acute cerebral ischemia in 76.2% and intracranial hemorrhage in 23.7%. Acute cerebral ischemia (ACI) had a unimodal distribution with peak onset at midday (12:00-12:59); intracerebral hemorrhage (ICH) a bimodal distribution with peaks at mid-morning (08:00-08:59) and early evening (18:00-18:59). Events were markedly reduced in early morning, with only 3.4% starting in the first 25% of the day. The proportion of hemorrhagic was higher in the first 8h of the day (00:00-07:59) than the remaining 16h, 33.3% vs 22.5%, p=0.006. ACI and ICH patients displayed fairly homogeneous vascular risk factors, presenting deficit severity, and initial brain imaging findings across all time periods. Discussion: There is marked, more than 10-fold, circadian variation in onset of acute cerebrovascular disease, and circadian variation in the ratio of ischemic to hemorrhagic neurovascular events. These findings can inform resource planning for regional systems of acute stroke care

Quantifying the amount of greater brain ischemia protection time with pre-hospital vs. in-hospital neuroprotective agent start

The objective of this study is to quantify the increase in brain-under-protection time that may be achieved with pre-hospital compared with the post-arrival start of neuroprotective therapy among patients undergoing endovascular thrombectomy. In order to do this, a comparative analysis was performed of two randomized trials of neuroprotective agents: (1) pre-hospital strategy: Field administration of stroke therapy-magnesium (FAST-MAG) Trial; (2) in-hospital strategy: Efficacy and safety of nerinetide for the treatment of acute ischemic stroke (ESCAPE-NA1) Trial. In the FAST-MAG trial, among 1,041 acute ischemic stroke patients, 44 were treated with endovascular reperfusion therapy (ERT), including 32 treated with both intravenous thrombolysis and ERT and 12 treated with ERT alone. In the ESCAPE-NA1 trial, among 1,105 acute ischemic stroke patients, 659 were treated with both intravenous thrombolysis and ERT, and 446 were treated with ERT alone. The start of the neuroprotective agent was sooner after onset with pre-hospital vs. in-hospital start: 45 m (IQR 38-56) vs. 122 m. The neuroprotective agent in FAST-MAG was started 8 min prior to ED arrival compared with 64 min after arrival in ESCAPE-NA1. Projecting modern endovascular workflows to FAST-MAG, the total time of "brain under protection" (neuroprotective agent start to reperfusion) was greater with pre-hospital than in-hospital start: 94 m (IQR 90-98) vs. 22 m. Initiating a neuroprotective agent in the pre-hospital setting enables a faster treatment start, yielding 72 min additional brain protection time for patients with acute ischemic stroke. These findings provide support for the increased performance of ambulance-based, pre-hospital treatment trials in the development of neuroprotective stroke therapies

Abstract WP174: A Large-Scale Perfusion Imaging Atlas of Subacute Ischemia in MCA Atherosclerotic Stenosis

Background: Impaired perfusion may be an important determinant of outcomes in intracranial atherosclerotic disease (ICAD). CT and MRI perfusion imaging patterns of stenosis due to MCA ICAD have not been studied in detail. We characterized CT and MRI perfusion imaging measures of subacute ischemia subjects with MCA stenosis to create a novel atlas and define specific blood flow parameters. Methods: A retrospective, 5-year, analysis of consecutive ICAD patients evaluated with CT or MRI perfusion imaging for recent TIA or stroke (0-7 days) due to sub-occlusive (50-99%) MCA stenosis was conducted. CT/MRI volumes of core and hypoperfusion (>5 ml) were extracted with RAPID (iSchemaView, Inc.) and analyzed with respect to clinical variables. Descriptive statistics were used to quantify and map patterns of impaired perfusion. Results: 194 (median age 71, range 30-102 years; 53% women) patients with subacute ischemia were evaluated with MRI (n=161) or CT (n=33) perfusion imaging. Median initial NIHSS was 5 and median inpatient length of stay (LOS) was 4 (1-42) days. Hypoperfusion with Tmax>4s delay volumes (median 66.5 ml, mean 107.5 ml) were noted in 162 (84%) patients, Tmax>6s delay volumes (median 11.0 ml, mean 41.5 ml) in 118 (61%), Tmax>8s delay volumes (median 0 ml, mean 23.4 ml) in 81 (42%) and Tmax>10s delay volumes (median 0 ml, mean 16.9 ml) in 61 (31%). Hypoperfusion intensity ratios (Tmax>10s/Tmax>6s) were median 0.08 and mean 0.24. Ischemic core volumes on MRI (ADC6s hypoperfusion was unrelated to initial NIHSS (r=0.17, p=NS) or LOS (r=0.11, p=NS). Conclusions: Hypoperfusion is common in recently symptomatic ICAD patients with MCA stenosis. Tmax delay volumes and hypoperfusion intensity ratios are distinct from acute MCA occlusion. Mapping and understanding these specific patterns of perfusion will be instrumental in planning future ICAD trials

Paramedic Global Impression of Change During Prehospital Evaluation and Transport for Acute Stroke.

Background and Purpose- The prehospital setting is a promising site for therapeutic intervention in stroke, but current stroke screening tools do not account for the evolution of neurological symptoms in this early period. We developed and validated the Paramedic Global Impression of Change (PGIC) Scale in a large, prospective, randomized trial. Methods- In the prehospital FAST-MAG (Field Administration of Stroke Therapy-Magnesium) randomized trial conducted from 2005 to 2013, EMS providers were asked to complete the PGIC Scale (5-point Likert scale values: 1-much improved, 2-mildly improved, 3-unchanged, 4-mildly worsened, 5-much worsened) for neurological symptom change during transport for consecutive patients transported by ambulance within 2 hours of onset. We analyzed PGIC concurrent validity (compared with change in Glasgow Coma Scale, Los Angeles Motor Scale), convergent validity (compared with National Institutes of Health Stroke Scale severity measure performed in the emergency department), and predictive validity (of neurological deterioration after hospital arrival and of final 90-day functional outcome). We used PGIC to characterize differential prehospital course among stroke subtypes. Results- Paramedics completed the PGIC in 1691 of 1700 subjects (99.5%), among whom 635 (37.5%) had neurological deficit evolution (32% improvement, 5.5% worsening) during a median prehospital care period of 33 (IQR, 27-39) minutes. Improvement was associated with diagnosis of cerebral ischemia rather than intracranial hemorrhage, milder stroke deficits on emergency department arrival, and more frequent nondisabled and independent 3-month outcomes. Conversely, worsening on the PGIC was associated with intracranial hemorrhage, more severe neurological deficits on emergency department arrival, more frequent treatment with thrombolytic therapy, and poor disability outcome at 3 months. Conclusions- The PGIC scale is a simple, validated measure of prehospital patient course that has the potential to provide information useful to emergency department decision-making. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00059332

Impaired Distal Perfusion Predicts Length of Hospital Stay in Patients with Symptomatic Middle Cerebral Artery Stenosis

Perfusion imaging can risk stratify patients with symptomatic intracranial stenosis. We aim to determine the association between perfusion delay and length of hospital stay (LOS) in symptomatic middle cerebral artery (MCA) stenosis patients. This is a retrospective study of consecutive patients admitted to a comprehensive stroke center over 5 years with ischemic stroke or transient ischemic attack (TIA) within 7 days of symptom onset due to MCA stenosis (50-99%) and underwent perfusion imaging. Patients were divided into three groups: mismatch volume ≥ 15 cc based on T max > 6 second delay, T max 4-6 second delay, and <4 second delay. The outcome was LOS, both as a continuous variable and categorical (≥7 days [prolonged LOS] vs. <7 days). We used adjusted regression analyses to determine the association between perfusion categories and LOS. One hundred and seventy eight of 194 patients met the inclusion criteria. After adjusting for age and NIHSS, T max >6 second mismatch was associated with prolonged LOS (OR 2.94 95% CI 1.06-8.18; P = .039), but T max 4-6 second was not (OR 1.45 95% CI .46-4.58, P = .528). We found similar associations when LOS was a continuous variable for T max > 6 second (β coefficient = 2.01, 95% CI .05-3.97, P = .044) and T max 4-6 second (β coefficient = 1.24, 95% CI -.85 to 3.34, P = .244). In patients with symptomatic MCA stenosis, T max > 6 second perfusion delay is associated with prolonged LOS. Prospective studies are needed to validate our findings

Abstract P575: Impaired Distal Perfusion Predicts In-Hospital Outcome in Patients With Symptomatic Middle Cerebral Artery Stenosis

Background: Perfusion imaging is increasingly used to risk stratify patients with symptomatic intracranial stenosis. Length of hospital stay (LOS) in patients with ischemic stroke is a surrogate marker of increased morbidity. We aim to determine the association between perfusion delay on T max ( 6 sec) on perfusion weighted imaging and LOS in patients with symptomatic middle cerebral artery (MCA) stenosis. Methods: We included consecutive patients with left MCA stenosis admitted with ischemic stroke or TIA 6 sec delay, mismatch volume ≥ 15 mL based on T max 4-6 sec delay, and neither of the above mismatch patterns. The primary outcome was LOS, both as a continuous variable and categorical (≥ 7 days (prolonged LOS) vs. 6 sec and 31.3% had a mismatch volume ≥ 15 mL based on T max 4-6 sec and the median (IQR) LOS was 4 days (2-8). After adjusting for age and NIHSS, T max > 6 sec mismatch definition was associated with prolonged LOS (OR 2.90 95% CI 1.06-8.18; p=0.039) but T max 4-6 sec definition was not (OR 1.45 95% CI 0.46-4.58, p=0.528), without any interaction based on perfusion imaging modality (p interaction = 0.568). We found similar associations when LOS was considered as a continuous variable for T max > 6 sec (β coefficient=2.01, 95% CI 0.05-3.97, p=0.044) and T max 4-6 sec (β coefficient=1.24, 95% CI -0.85-3.34, p=0.244). In receiver operating curves, the optimal mismatch volume for T max > 6 sec was 10 mL (sensitivity 0.61 and specificity 0.63) whereas for T max 4-6 sec it was 39 mL (sensitivity 0.61 specificity 0.56). Conclusion: In patients with recently symptomatic MCA stenosis, the T max > 6 sec definition for mismatch, but not T max 4-6 sec, is associated with prolonged LOS. Prospective studies are needed to validate our findings and define the optimal mismatch threshold in patients with symptomatic MCA stenosis

Abstract P314: Mechanisms of Intracranial Atherosclerotic Disease Drive Hypoperfusion Patterns

Background: In patients with symptomatic intracranial atherosclerotic disease (ICAD), borderzone infarct pattern and perfusion mismatch have each been shown to independently predict recurrent strokes, which may reflect the shared underlying mechanism of hypoperfusion distal to the intracranial atherosclerosis. As such, we hypothesized that perfusion volumes and patterns may correlate with various ICAD subtypes. Methods: A retrospective, 5-year analysis of consecutive ICAD patients with perfusion imaging for acute strokes (0-24 hours) due to sub-occlusive (50-99%) stenosis was conducted. The following subtypes were assigned based on the infarct pattern seen on the diffusion-weighted imaging (DWI): perforator, borderzone, and thromboembolic. Core volume on MRI and perfusion parameters on CT or MR perfusion, obtained concurrently or within 12 hours of MR DWI, were studied in each group. Results: 42 patients (57% women, mean age 71±13 years old) with acute strokes received MRI imaging upon initial presentation. 15 were found with borderzone, 12 perforator, and 15 with thromboembolic pattern on DWI. Across all ICAD subtypes, median core volume (ADC 4s and Tmax >6s delay volumes was significantly higher in the thromboembolic and borderzone infarct patterns compared to the perforator subtype ( Figure 1 ). The volume difference between Tmax >4s and Tmax >6s (Δ Tmax>4s - Tmax>6s) was higher in the borderzone subtype compared to thromboembolism when analyzed pairwise. Conclusion: Core volume in ischemic strokes secondary to symptomatic ICAD is minimal. TMax>4 and TMax>6 parameters vary across the different ICAD patterns, with significantly large Tmax>4 delay volumes in the borderzone profile. Perfusion mapping may further elucidate hemodynamic mechanisms underlying ICAD

Intracranial atherosclerotic disease mechanistic subtypes drive hypoperfusion patterns

In symptomatic intracranial atherosclerotic stenosis (ICAS), borderzone infarct pattern and perfusion mismatch are associated with increased risk of recurrent strokes, which may reflect the shared underlying mechanism of hypoperfusion distal to the intracranial atherosclerosis. Accordingly, we hypothesized a correlation between hypoperfusion volumes and ICAS infarct patterns based on the respective underlying mechanistic subtypes. We conducted a retrospective analysis of consecutive symptomatic ICAS cases, acute strokes due to subocclusive (50%-99%) intracranial stenosis. The following mechanistic subtypes were assigned based on the infarct pattern on the diffusion-weighted imaging: Branch occlusive disease (BOD), internal borderzone (IBZ), and thromboembolic (TE). Perfusion parameters, obtained concurrently with the MRI, were studied in each group. A total of 42 patients (57% women, mean age 71 ± 13 years old) with symptomatic ICAS received MRI within 24 h of acute presentation. Fourteen IBZ, 11 BOD, and 17 TE patterns were identified. IBZ pattern yielded higher total T > 4 s and T > 6 s perfusion delay volumes, as well as corresponding T  > 4 s and T  > 6 s mismatch volume, compared to BOD. TE pattern exhibited greater median T  > 6 s hypoperfusion delay in volume compared to BOD. In IBZ versus TE, the volume difference between T > 4 s and T > 6 s (Δ T  > 4 s - T  > 6 s) was substantially greater. ICAS infarct patterns, in keeping with their respective underlying mechanisms, may correlate with distinct perfusion profiles

Neurologic Improvement in Acute Cerebral Ischemia

Background and objectivesInvestigations of rapid neurologic improvement (RNI) in patients with acute cerebral ischemia (ACI) have focused on RNI occurring after hospital arrival. However, with stroke routing decisions and interventions increasingly migrating to the prehospital setting, there is a need to delineate the frequency, magnitude, predictors, and clinical outcomes of patients with ACI with ultra-early RNI (U-RNI) in the prehospital and early postarrival period.MethodsWe analyzed prospectively collected data of the prehospital Field Administration of Stroke Therapy-Magnesium (FAST-MAG) randomized clinical trial. Any U-RNI was defined as improvement by 2 or more points on the Los Angeles Motor Scale (LAMS) score between the prehospital and early post-emergency department (ED) arrival examinations and classified as moderate (2-3 point) or dramatic (4-5 point) improvement. Outcome measures included excellent recovery (modified Rankin Scale [mRS] score 0-1) and death by 90 days.ResultsAmong the 1,245 patients with ACI, the mean age was 70.9 years (SD 13.2); 45% were women; the median prehospital LAMS was 4 (interquartile range [IQR] 3-5); the median last known well to ED-LAMS time was 59 minutes (IQR 46-80 minutes), and the median prehospital LAMS to ED-LAMS time was 33 minutes (IQR 28-39 minutes). Overall, any U-RNI occurred in 31%, moderate U-RNI in 23%, and dramatic U-RNI in 8%. Any U-RNI was associated with improved outcomes, including excellent recovery (mRS score 0-1) at 90 days 65.1% (246/378) vs 35.4% (302/852), p &lt; 0.0001; decreased mortality by 90 days 3.7% (14/378) vs 16.4% (140/852), p &lt; 0.0001; decreased symptomatic intracranial hemorrhage 1.6% (6/384) vs 4.6% (40/861), p = 0.0112; and increased likelihood of being discharged home 56.8% (218/384) vs 30.2% (260/861), p &lt; 0.0001.DiscussionU-RNI occurs in nearly 1 in 3 ambulance-transported patients with ACI and is associated with excellent recovery and decreased mortality at 90 days. Accounting for U-RNI may be useful for routing decisions and future prehospital interventions. TRIAL REGISTRATION INFORMATION: clinicaltrials.gov. Unique identifier: NCT00059332