Field Administration Of Stroke Therapy-Magnesium Research Articles

Abstract TP235: Prehospital Clinical Deterioration Predicts Further Deterioration in Acute Stroke

Background: Studies of neurologic deterioration in stroke have primarily focused on the acute period 24 hours after arrival. We sought to determine whether prehospital/early ED hyper-acute deterioration portends subsequent deterioration in the 24 hour acute period, as well as other prehospital factors that may predict subsequent deterioration. Methods: All subjects were enrolled in the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial. Hyper-acute neurologic deterioration was defined as Glasgow Coma Scale (GCS) decreasing ≥2 points from paramedic to ED evaluation, acute neurologic deterioration was defined as ≥4 point increase on the NIH Stroke Scale (NIHSS) from ED evaluation to 24 hours post-arrival. Other prehospital factors investigated included age, race, sex, WBC, serum glucose, arrival NIHSS, systolic blood pressure (SBP), body temperature, intracerebral hemorrhage (ICH), hypertension, smoking, diabetes, and previous stroke. Results: Of 1,643 patients, 184 (11.2%) experienced acute 24-hour deterioration. Among deteriorators; 45 % were female and mean age (SD) was 70 (±13.3) years. Median last-known-well time to assessments were: prehospital GCS 25 (IQR 15-46) mins, ED arrival GCS and NIHSS 149 (IQR 120-180) minutes and follow-up (24-hour) NIHSS 26 (IQR 18-30) hours. On multivariate analysis, hyper-acute deterioration increased the odds of subsequent acute neurological deterioration (OR = 2.24, p = 0.010, 95% CI 1.21-4.14). Other factors independently associated with acute 24-hour deterioration were ICH, arrival NIHSS, serum glucose level, SBP and body temperature (see Table 1). Conclusion: Hyper-acute deterioration is associated with increased odds of acute neurological deterioration in the subsequent 24-hour period.

Abstract WP341: Imaging Predictors of Intracerebral Hematoma Expansion in Hyperacutely-Presenting Patients

Background: Several noncontrast CT findings may increase risk of intracerebral hemorrhage (ICH) expansion, including ICH volume, location, margin irregularity, heterogeneity, the blend sign, and leukoaraioisis. Hyperacute EMS-transported patients have more frequent hematoma progression and may have distinctive predisposing imaging features. Methods: We analyzed consecutive patients enrolled in the NIH Phase 3 Field Administration of Stroke Therapy - Magnesium (FAST-MAG) prehospital trial and who had both ED-arrival and 6 to 48h follow-up brain CT or GRE-MRI. Hematoma expansion (HE) was defined as hematoma volume growth by ≥ 6ml. Results: Among 262 ICH patients meeting entry criteria, age was 64.8 (±12.9), 32.4% were female, arrival GCS was median 15 (IQR 11-15), and arrival NIHSS median 15 (IQR 9-24). Initial imaging was with CT in 95.8% and GRE-MRI in 4.2%. Median time from last known well to first imaging was 80 min (IQR 66-98) and from first to follow-up imaging 16.7 hr (IQR 11.3-22.3). Overall, 30.5% of patients experienced hematoma expansion. Univariate imaging predictors of HE were: hematoma volume, 25.1 vs 18.6 ml, p<0.001; perihematomal edema volume, 16.0 vs 11.7 ml, p<0.001; basal ganglia location, 63.7% vs 46.2%, p=0.009; moderate-severe midline shift, 31.3% vs 12.6%, p<0.001; greater hematoma shape irregularity, 2.8 vs 2.3, p=0.01; and high hematoma density heterogeneity, 62.5% vs 40.4%, p=0.001. Intraventricular hemorrhage, leukoaraiosis, and blend sign were not associated with HE. In multivariable analysis, independent imaging predictors of HE were: moderate-severe midline shift (aOR 3.7, 95%CI 1.4-9.5) and hematoma density heterogeneity (aOR 2.2, 95%CI 1.1-4.4). HE was associated with substantially reduced 90d functional independence (mRS 0-2, 15.0% vs 36.5%, p=0.001) and increased 90d mortality (46.3% vs 11.0%, p<0.001). Conclusions: Among hyperacute, EMS-transported intracerebral hemorrhage patients, several conventional and novel imaging findings on noncontrast CT are associated with hematoma expansion. Key independent predictors of hematoma growth are early evidence of moderate-severe midline shift and hematoma density heterogeneity.

Abstract WP337: Frequency, Determinants, and Outcomes of Intracerebral Hemorrhage Expansion in Hyperacute EMS-Transported Patients

Background: As clinical and research interventions for intracerebral hemorrhage (ICH) migrate to the prehospital setting, patients are being treated earlier than ever before. The frequency, determinants, and outcomes of hematoma expansion among hyperacute, EMS-transported patients have not been previously characterized. Methods: We analyzed all ICH patients enrolled in the NIH Phase 3 Field Administration of Stroke Therapy - Magnesium (FAST-MAG) prehospital trial who had both ED-arrival and 6 to 48-hour follow-up brain CT or GRE-MRI. Hematoma expansion (HE) was defined as hematoma volume growth by ≥ 6 ml. Results: Among 262 ICH patients meeting entry criteria, age was 64.8±12.9, 32.4% were female, and last known well to ED arrival was 52 mins (IQR 44-70). Hematoma expansion occurred in 80 (30.5%). Clinical predictors of HE included: anticoagulant use at onset, 11.3% vs 3.8%, p=0.03; lower level of consciousness at ED arrival, median GCS 14 vs 15, p<0.001; greater neurologic deficit at ED arrival, NIHSS 21 vs 13, p<0.001, basal ganglia ICH location, 63.7% vs 46.2%, p =0.009; and shorter interval from onset to first imaging, 80.2 vs 84.5 mins, p=0.04. Features not predictive of HE in this hyperacute cohort included: age, blood pressure, and intraventricular hemorrhage extension on initial imaging. In multivariable analysis, independent predictors of HE were: anticoagulants at onset (aOR 4.2, 95%CI 1.5-12.9), GCS at arrival (aOR 1.2, 95%CI 1.0 – 1.4), and NIHSS at arrival (aOR 1.1, 95%CI 1.1 – 1.2), with c statistic 0.73. HE was associated with increased early (48h) neurologic deterioration (45.6% vs 15.5%, aOR 5.3, 95%CI 2.8-10.1), reduced 90d functional independence (mRS 0-2, 15.0% vs 36.5%, aOR 0.27, 95%CI 0.13-0.56), and increased 90d mortality (46.3% vs 11.0%, aOR 8.1, 95%CI 4.0-16.6). Conclusions: Hematoma expansion is frequent among hyperacute, EMS-transported ICH patients, occurring in more than 3 in 10 patients. Anticoagulant use, reduced level of consciousness, and greater neurologic deficit are independent determinants of HE, and collectively predict HE moderately well. Hematoma expansion is clinically consequential, associated with a 5-fold increase in odds of early neurology deterioration and 8-fold increase in odds of death by 90 days.

Abstract WP228: Imaging Findings Associated With Ultra-Early Neurological Deterioration in EMS-Transported Intracerebral Hemorrhage Patients

Background: With the rise of prehospital intervention, intracerebral hemorrhage (ICH) management is increasingly migrating to the field setting. Ultra-early neurologic deterioration (U-END), during prehospital transport and the first minutes after ED arrival, is a novel target for therapy, imaging determinants could provide useful pathophysiologic insights for treatment. Methods: We analyzed all ICH patients enrolled in the NIH Phase 3 Field Administration of Stroke Therapy - Magnesium (FAST-MAG) prehospital trial who had both ED-arrival and 6-48h follow-up brain CT or GRE-MRI. Deterioration was defined as worsening by ≥2 on the Glasgow Coma Scale (GCS), performed serially by paramedics in the field, upon ED arrival, and early in the ED course. Results: Among 213 ICH patients, age was 65.4 (±13.4) and 33.3% were female. Timing from last know well (LKW) to early serial GCS assessments were: field GCS by paramedic, 23 mins (IQR 14-39); ED arrival GCS, 57 mins (IQR 45-75); and early ED course GCS, 89 mins (IQR 65-107). Initial brain imaging was performed 80 min (IQR 66-98) after LKW, using noncontrast CT in 96%. Overall, 38.5% of ICH patients experienced ultra-early neurological deterioration, including 12.7% in prehospital phase only, 12.2% in early ED course only, and 10.3% in both. Initial imaging findings associated with U-END were: larger hematoma volume 28.3 vs 17.6 cc, p<0.001; larger edema volume 15.4 vs 9.8 cc, p=0.001; moderate-severe midline shift 45.5% vs 6.8%, p<0.001; hematoma irregularity, 53.2% vs 33.0%, p=0.002; hematoma heterogeneity, 63.6% vs 40.8%, p=0.001; and basal ganglia location, 64.9% vs 46.3%, p=0.006. In multivariate analysis, U-END in the prehospital phase was associated with hematoma margin irregularity, OR 1.5 (95%CI 1.1-2.2); while U-END during the early ED course was associated with midline shift, OR 7.2 (95%CI 1.9-26.4) and hematoma margin irregularity, OR 2.3 (95%CI 1.1 - 5.1). Conclusions: ICH patients with ultra-early neurological deterioration have larger hematoma and edema volumes on initial brain imaging. Greater hematoma shape irregularity suggests ongoing, multiphasic and multifocal, bleeding is an important, and potentially avertable, contributor to prehospital and early ED course deterioration.

Abstract WMP60: Serial Body Temperature Evaluation and Long-Term Clinical Outcomes in Stroke

Background: Elevated body temperature is a known marker of poor outcome in stroke. Some studies have shown that elevated body temperature early in the course of stroke is associated with better outcomes. We sought to characterize the relationship of body temperature and long-term clinical outcomes by evaluating serial measurements over 24 hours. Methods: All subjects were enrolled <2 hours after stroke symptom onset into the Phase 3 NIH Field Administration of Stroke Therapy Magnesium (FAST-MAG) clinical trial testing magnesium for prehospital neuroprotection. Presenting temperature in the emergency room and follow-up temperatures at 8, 16 and 24 hours after arrival were recorded. Clinical outcome was measured using the modified Rankin Scale at 90 days with last observation carried forward. Mean temperature was compared for each outcome on the modified Rankin Scale (mRS) utilizing ANOVA. Results: Among the 1700 enrolled patients 1586 (93%) had temperature recorded on ED arrival, 1594 at 8 hours, 1611 at 16 hours, 1594 at 24 hours. Mean age was 69 years, 43% were women, final diagnosis cerebral ischemia in 73.3%, intracranial hemorrhage in 22.8%, and mimic in 3.9%. At presentation mean body temperature was higher among those experiencing better long-term outcomes (Figure 1A). As of 8 hours and continuing through all subsequent measures worse outcome across the modified Rankin Scale spectrum was associated with higher body temperature (Figure 1B-D). Conclusions: Although higher body temperature at presentation was noted in subjects achieving better long-term outcomes, subsequent measures as of 8 hours demonstrated higher body temperatures in those experiencing worse long-term outcomes.

Abstract TMP85: Serial Body Temperature and Acute Clinical Deterioration in Stroke

Background: Studies on the effect of body temperature on outcome in stroke are conflicting with most demonstrating that elevated body temperature is associated with poor outcome in stroke, and some indicating that very early body temperature elevation is associated with better outcomes. We sought to characterize the relationship of body temperature and clinical deterioration by evaluating serial measurements over 24 hours. Methods: All subjects were enrolled <2 hours after stroke symptom onset into the Phase 3 NIH Field Administration of Stroke Therapy Magnesium (FAST-MAG) clinical trial testing magnesium for prehospital neuroprotection. Presenting temperature in the emergency room and follow-up temperatures at 8, 16 and 24 hours after arrival were recorded. Acute deterioration was defined as 4 point worsening on NIHSS from presentation to 24 hours. Mean temperature was compared at all time points for deteriorators and non-deteriorators utilizing t-test. All measures were in °C. Results: Of 1700 subjects 1586 (93%) had temperature recorded on ED arrival, 1594 at 8 hours, 1611 at 16 hours, and 1594 at 24 hours (1385 had all 4 recorded). Mean age was 69 years, 43% were women, final diagnosis cerebral ischemia in 73.3%, intracranial hemorrhage in 22.8%, and mimic in 3.9%. Mean body temperature for deteriorators was not different at presentation (36.5 vs. 36.6, p=0.221), but was significantly higher at 8 hours (36.8 vs. 36.6, p<0.001), at 16 hours (37.0 vs. 36.7, p<0.001) and 24 hours (37.0 vs. 36.7, p<0.001). Of cerebral ischemia cases (N=1150) the same temperature relationship held true (presentation: 36.6 vs. 36.6, p=0.744, 8-hours: 36.7 vs. 36.6 p=0.002, 16 hours: 36.8 vs 36.6 p<0.001, 24 hours: 36.9 vs. 36.7, p<0.001). In cases of ICH elevated temperature was not significantly higher until 16 hours after arrival (presentation: 36.5 vs. 36.6, p=0.173, 8-hour: 36.9 vs. 36.8 p=0.313, 16 hour: 37.2 vs. 36.9 p<0.001, 24-hour: 37.1 vs 36.9 p=0.036). Conclusions: Higher body temperatures were noted in those experiencing clinical deterioration 8 hours after arrival. Early elevations in body temperature may be a predictor of clinical deterioration in acute stroke.

Association Between Hyperacute Stage Blood Pressure Variability and Outcome in Patients With Spontaneous Intracerebral Hemorrhage.

Increased blood pressure (BP) variability, in addition to high BP, may contribute to adverse outcome in intracerebral hemorrhage. However, degree and association with outcome of BP variability (BPV) in the hyperacute period, 15 minutes to 5 hours after onset, have not been delineated. Among consecutive patients with intracerebral hemorrhage enrolled in the FAST-MAG trial (Field Administration of Stroke Therapy-Magnesium), BPs were recorded by paramedics in the field and during the first 24 hours of hospital course. BP was analyzed in the hyperacute period, from 0 to 4-6 hours, and in the acute period, from 0 to 24-26 hours after onset. BPV was analyzed by SD, coefficient of variation, and successive variation. Among 386 patients with intracerebral hemorrhage, first systolic BP at median 23 minutes (interquartile range, 14-38.5) after onset was median 176 mm Hg, second systolic BP on emergency department arrival at 57 minutes (interquartile range, 45-75) after onset was 178 mm Hg, and systolic BP 24 hours after arrival was 138 mm Hg. Unfavorable outcome at 3 months (modified Rankin Scale, 3-6) occurred in 270 (69.9%). Neither mean nor maximum systolic BP was associated with outcome in multivariable analysis. However, all 3 parameters of BPV, in both the hyperacute and the acute stages, were associated with poor outcome. In the hyperacute phase, BPV was associated with poor outcome with adjusted odds ratios of 3.73 for the highest quintile of SD, 4.78 for the highest quintile of coefficient of variation, and 3.39 for the highest quintile of successive variation. BPV during the hyperacute first minutes and hours after onset in patients with intracerebral hemorrhage was independently associated with poor functional outcome. Stabilization of BPV during this vulnerable period, in the pre-hospital and early emergency department course, is a potential therapeutic target for future clinical trials. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

A Dedicated Spanish Language Line Increases Enrollment of Hispanics Into Prehospital Clinical Research.

Novel methods are needed to reduce the disparity of Hispanic enrollment in stroke clinical trials. Prehospital enrollment using a dedicated Spanish language line may help overcome this bias. Subjects or legally authorized representatives provided information on race and ethnicity for all cases enrolled in the FAST-MAG clinical trial (Field Administration of Stroke Therapy-Magnesium), a prehospital phase 3 randomized study of intravenous magnesium for neuroprotection. One of 2 in-ambulance cell phones (in English or Spanish) was used to obtain informed content in the field. We describe the yield and characteristics of subjects enrolled via Spanish line. There were 1700 subjects enrolled from 2005 to 2012, of which 402 (24%) identified as Hispanic ethnicity. Study racial makeup was 1325 (78%) white, 219 (13%) black, and 139 (8%) Asian. The dedicated Spanish line was used for 195 (12%) enrollments. Spanish-line enrollments were younger (65 versus 70 years old; P<0.001), more likely to identify as Hispanic (98% versus 14%; P<0.001), and more likely to present with intracerebral hemorrhage (36% versus 21%; P<0.001). The use of a dedicated Spanish language enrollment line allowed for greater enrollment of Hispanics, a population with significantly different baseline characteristics. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

Abstract WP245: Hyperacute Blood Pressure Variability is Associated with Early Neurological Deterioration

Background: Increased blood pressure variability (BPV) has been associated with worse outcomes in acute stroke. The effect of hyperacute (&lt;4 hours) BPV on early neurologic deterioration (END) has not been described. Objective: To investigate whether BPV in the first hours after stroke onset is associated with END from prehospital evaluation to presentation at the emergency department Methods: All patients enrolled in the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) phase 3 trial were included. FAST-MAG was a multicenter, randomized, double-blind, placebo-controlled study looking at whether initiation of magnesium sulfate (20 grams/24 hours) in the prehospital setting of acute stroke would reduce disability. Study agent was initiated prior to hospital arrival &lt; 2 hours from symptom onset. BPV was defined as the standard deviation of systolic blood pressure of all readings obtained by 4 hours after initiation of study agent. END was diagnosed as Glasgow Coma Scale (GCS) decrease by ≥ 2 points between the prehospital evaluation and post-emergency department arrival assessment by a study nurse. Results: There were 1,700 cases evaluated by paramedics 24 minutes (15-45 IQR), and by study nurses 150 minutes (120-180) after symptom onset with a median of 6 (IQR 5-6) BP readings. The mean (±SD) age was 69±13 years, 42.6% were women, and the median prehospital GCS was 15 (IQR 14-15). The final diagnosis was cerebral ischemia in 73.3% of patients, intracranial hemorrhage in 22.8%, and a stroke-mimicking condition in 3.9%. END was seen in 202 (12%) of subjects, with higher rates noted in those with intracerebral hemorrhage (ICH) compared to cerebral ischemia (31% vs 6%). Overall, there was greater BPV in patients with END (23mmHg vs 15mmHg, p&lt;0.001). Blood pressure variability was greater in cases of cerebral ischemia with END (N=1,245, 18mmHg vs 15mmHg, p=0.004) and in ICH cases with END (N=387, 23mmHg vs 15mmHg, p&lt;0.001). Conclusion: Greater blood pressure variability is associated with early neurologic deterioration in patients with cerebral ischemia and ICH evaluated &lt;2 hours from symptom onset.

Abstract TP234: The Effect of Early Treatment with Magnesium on Blood Pressure Variability in Hyperacute Stroke

Background: Increased blood pressure (BP) variability has been associated with worse outcomes in acute stroke. Magnesium has been shown to have both vasoactive and cardio-active properties that could potentially attenuate blood pressure variability emergently. Objective: To investigate whether intravenous magnesium sulfate can minimize blood pressure variability in hyperacute stroke. Methods: All patients with a diagnosis of stroke (cerebral ischemia, intracerebral hemorrhage) enrolled in the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) phase 3 trial were included. FAST-MAG was a multicenter, randomized, double-blind, placebo-controlled study looking at whether initiation of magnesium sulfate (20 grams/24 hours) in the prehospital setting of acute stroke would reduce disability. Study agent was initiated prior to hospital arrival &lt; 2 hours from symptom onset. Blood pressure variability was defined as the standard deviation (SD) of systolic blood pressure of all readings obtained by 4 hours after initiation of study agent. BP variability was compared using t-test of the bootstrapped SD between groups. Results: In total, 1,700 patients were included in the study with a median of 6 (IQR 5-6) BP readings, of which 1,245 had cerebral ischemia (CI), 387 had intracerebral hemorrhage (ICH), and 68 had stroke mimics. Of those with CI, 632 received magnesium and 613 placebo; the standard deviation of systolic blood pressure was not significantly different between those who received magnesium and those who did not (14.9mmHg vs. 15.3mmHg, p=0.315). In the ICH population (195 magnesium, 192 placebo), magnesium treatment also did not affect BP variability (22.5mmHg vs. 21.1mmHg, p=0.197). For the overall study group, hyperacute magnesium treatment had no effect on blood pressure variability (16.7mmHg vs. 16.6mmHg, p=.907). Conclusion: Treatment with magnesium did not reduce BP variability in hyperacute stroke.

Abstract WP257: Accuracy of Pre-enrollment Last Known Well Time in a Large Prehospital Stroke Clinical Trial

Background: Clinical trials of stroke therapies require accurate documentation of last known well time (LKWT) to account for injury accumulation prior to treatment start. For prehospital studies, this requirement is particularly challenging, as paramedic-determined and final-determined LKWTs in routine practice are concordant (within 15 mins) in only half of cases. We sought to determine the accuracy of LKWT obtained in the field by a two-tier enrollment system of study-trained paramedics and cellphone-connected physician-investigators. Methods: Paramedics screened consecutive transports for participation in the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) clinical trial. Paramedic screening criteria included LKWT &lt;2 hours. Physician-investigators by cellphone confirmed or refined the LKWT after conversation with paramedics and patients or legally authorized representative. Prehospital LKWT was compared with post-arrival LKWT determined by trained study nurses after ED arrival by speaking with patients, family and other sources. We describe the number of enrollment calls with inaccurate LKWT at the paramedic-screening level and at the post paramedic plus physician-investigator telephone screening level. Results: A total of 4458 post-screening enrollment calls were made by paramedics from January 2005 to December 2012 of which 539 (12%) were determined by physician-instigators to have inaccurate LKWT leading to non-enrollment. Of the remaining 3919 calls, 1700 led to enrollments in the study and 2219 were not enrolled for a reason other than inaccurate LKWT. Among enrolled cases, exact congruence between prehospital and post-arrival LKWTs occurred 72% (n=1220), concordance within 15 minutes in 87%, within 30 minutes in 93%, and within 1 hour in 97%. Among enrolled cases, final-determined LKWT was within the study entry window of 2h in 96.3%. Conclusions: A 2-tiered system of paramedic screening followed by physician-investigator cellphone assessment led to high congruence between prehospital-determined and post-arrival-determined of LKWT. This system can be used in future trials of prehospital, paramedic-in initiated stroke therapy when accuracy of LKWT is important for intervention evaluation.

Abstract WP256: High Rate of Subject Retention into Prehospital Stroke Research with Telephone-based Physician-investigator Driven Enrollment

Background: Explicit informed consent for prehospital research can be achieved by physician-investigators using cellular phones to communicate with potential subjects or legally authorized representatives (LAR). Subject retention into clinical trials is vital, and prehospital enrollment may be associated with higher rates of subject withdrawal than more traditional methods of enrollment. Objective: To describe rates of subject retention in a prehospital trial of acute stroke therapy and to determine if method of consent was associated with subject withdrawal. Methods: All subjects were enrolled in the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) clinical trial. Paramedics screen eligible subjects, contact the physician-investigator using dedicated in-ambulance cellular phone. Physician-investigators obtain explicit informed consent from the subject or on-scene LAR. In the later years of study, enrolment under exception from informed consent (EFIC) was permitted. The consent provider was given a consent form, which they reviewed with the physician investigator on the phone and signed prior to study initiation. Retention, defined as study subject completion without withdrawal. Results: There were 1700 subjects enrolled; 1,017 provided consent (60%), 662 enrolled via LAR (39%) and 21 via EFIC (1%). Of 1,700 patients, 1413 (83%) completed the 90-day cvisit, 265 (16%) died prior to the 90-day visit and 22 (1.3%) withdrew from the study before completion. Of the 22 cases what withdrew, 11 were lost to follow-up, 11 had the patient or LAR withdraw consent. There were no differences in rates of withdrawal by method of study enrolment: Self consent (n=14) 1.4%, LAR (n=8) 1.2%, EFIC (n=0) 0%. Potential factors related to higher rates of withdrawal were evaluated including language of consent (Spanish 4/165, 2.1%, English 18/1248, 1.2%), but none were significant. The most common reason for withdrawal of consent was family objection to continued participation in research. Conclusion: There was a high rate of retention when subjects were enrolled into prehospital stroke research using a phone-based method to obtain explicit consent. We were not able to identify factors associated with study withdrawal, likely due to high retention.

Abstract 118: Paramedic-Administered Los Angeles Motor Scale identifies Ischemic Stroke with Large Vessel Occlusion and Intracranial Hemorrhage for Routing to Comprehensive Stroke Centers and Compares Favorably to Other Screening Methods

Background: Considering the recent advances in endovascular thrombectomy and advances in neurocritical care of patients with intracranial hemorrhage (ICH), there is an urgent need to develop tools for paramedics to identify patients likely to benefit from direct routing to comprehensive stroke centers (CSC). We report prospective validation of the Los Angeles Motor Scale (LAMS) performed by paramedics in the field, and compare its performance with other proposed prehospital LVO-identification scales. Methods: We analyzed all subjects enrolled in the NIH Field Administration of Stroke Therapy -Magnesium (FAST-MAG) trial transported directly to an academic center with a policy of performing immediate CTA or MRA imaging for all likely strokes. Prehospital LAMS was performed by paramedics prior to field enrollment. Hospital arrival (HA) LAMS and NIHSS were performed by trained study nurses after ED arrival. RACE, PASS, and 3i SS scales were calculated from NIHSS items. LVO in a proximal cerebral artery (ICA, MCA M1 &amp; M2, Vertebral, Basilar and PCA P1 &amp; 2) was determined by 3 vascular neurologists with expertise in neuroimaging. An LVO or ICH were considered as CSC appropriate patients. Results: Among 94 patients, age was 68 (±13) and 49% were female. Final diagnoses were acute cerebral ischemia in 71 (76%), intracranial hemorrhage in 18 (19%), mimic in 5 (5%). Overall, 48 patients (68%) had LVO, including MCA (30), ICA (14), basilar (1), vertebral (1) and PCA (2), and 66 (70%) were CSC-appropriate (LVO or ICH). In prediction of LVO, prehospital LAMS had the highest sensitivity (71%) and moderate specificity (54%). 3i-SS had the highest specificity (83%) but lowest sensitivity (40%). In prediction of CSC-appropriate patients, prehospital LAMS had the highest sensitivity (69%) and 3i-SS had the highest specificity (93%) but lowest sensitivity (37%). When comparing receiver operating curves, PM LAMS had AUC of 0.761, HA RACE 0.752, HA 3i SS 0.732, and HA PASS 0.712. Conclusions: Prehospital LAMS score of 4 or higher identified CSC-appropriate patients with good sensitivity and moderate specificity, and performed similar to or better than other proposed scales. LAMS is easy to administer and reproducible, and widely used currently by paramedics nationwide.

Abstract TP233: Patterns, Determinants and Outcomes of Ultra-Early Neurological Deterioration (U-END) in Acute Ischemic Stroke

Background: The patterns and outcomes of deterioration during prehospital transport and the first phase of ED care are important for planning for diversion of acute cerebral ischemia (ACI) patients to designated stroke centers and design of prehospital treatment trials. Methods: We analyzed patients enrolled in the NIH Phase 3 Field Administration of Stroke Therapy - Magnesium (FAST-MAG) trial within 2h of last known well (LKW). Deterioration was defined as worsening by ≥2 on the Glasgow Coma Scale (GCS), performed serially by paramedics in the field, upon ED arrival, and after the early ED course. Results: Among 713 acute cerebral ischemia patients, age was 65.4 (±13.4), 45% female. Times from LKW to GCS assessments were: paramedic, 25 mins (IQR 15-46); ED arrival, 60 mins (IQR 48-82); and after early ED course, 83 mins (IQR 60-106). Overall, 16.3% experienced neurological deterioration, including 9.0% in prehospital phase only, 7.3% in early ED phase only, and none in both phases. Granular patterns of deficit progression were: Prehospital Sustained - prehospital deterioration, then stable early ED phase, 2.2% (16); Dippers - prehospital deterioration, then early ED improvement, 6.7% (48); Delayed - stable prehospital, then ED deterioration, 3.0% (22); and Peakers - prehospital improvement, then early ED deterioration, 4.2% (30) (Figure). Ischemic stroke patients who experienced any U-END had higher age, 73.2 vs 69.8, p&lt;0.01; lower prehospital GCS scores, 14 (IQR 11-15) vs 15 (IQR 14-15), p&lt;0.001; and greater prehospital focal weakness, LAMS 4.2 vs 3.6, p&lt;0.001. U-END was associated with higher rates of disability or death (mRS 2-6) at 90 days, 77.8% vs 53.8%, p&lt;0.001. Conclusions: Ultra-early neurological deterioration occurs in one-sixth of EMS-transported acute cerebral ischemia patients, and is associated with less favorable outcome. Early identification and effective management strategies are needed to reduce its occurrence.

Abstract 149: Patterns, Determinants and Outcomes of Ultra-early Neurological Deterioration (U-END) in Intracranial Hemorrhage

Background: The patterns and outcomes of deterioration during prehospital transport and the first phase of ED care are important for planning for design of prehospital intracranial hemorrhage (ICH) treatment trials. Methods: Patients were enrolled in the NIH Phase 3 Field Administration of Stroke Therapy - Magnesium (FAST-MAG) prehospital trial within 2h of last known well (LKW). Deterioration was defined as worsening by ≥2 on the Glasgow Coma Scale (GCS), performed serially by paramedics in the field, upon ED arrival, and after the early ED course Results: Among 213 patients with ICH, age was 65.4 (±13.4), 33.3% female. Times from LKW to GCS assessments were: paramedic, 23 mins (IQR 14-39); ED arrival, 57 mins (IQR 45-75); and after early ED course, 89 mins (IQR 65-107). Overall, 38.5% experienced neurological deterioration, including 12.7% in prehospital phase only, 12.2% in early ED phase only, and 10.3% in both. Granular patterns of deficit progression were: Prehospital Sustained - prehospital deterioration, then stable early ED phase, 6.1% (13); Dippers - prehospital deterioration, then early ED improvement, 6.6% (14); Delayed - stable prehospital, then ED deterioration, 12.2% (26); and Continuous - prehospital deterioration, then further deterioration in ED, 10.3% (22) (Figure). ICH patients who experienced any U-END had lower prehospital GCS scores, 15 (IQR 12-15) vs 15 (IQR 15-15), p&lt;0.001, greater prehospital focal weakness, LAMS 4.4 vs 3.9, p&lt;0.001, history of hypertension, 87.4% vs 74.9%, p&lt;0.001, higher ED SBP, 186 vs 174, p&lt;0.001, and larger ICH volume, 45.8 vs 21.8 cm 3 , p&lt;0.001. U-END was associated with higher dependence or death (mRS 3-6) at 90d, 90.1% vs 61.6%, p&lt;0.001. Conclusions: Ultra-early neurological deterioration occurs in more than one-third of EMS-transported ICH patients, is associated with elevated BP, and leads to unfavorable outcome. Clinical trials testing prehospital initiation of BP-lowering therapy for ICH are desirable.

Abstract 70: Importance of Both Self-consent and Proxy- consent Enrollments to Avoid Bias in Acute Stroke Randomized Trials

Background: Informed consent options for acute stroke randomized trials include self-consent from patients with retained competency, proxy consent from a legally authorized representative (LAR), and exception from informed consent in emergency circumstances (EFIC). Mechanisms other than self-consent trespass upon the ethical principle of autonomy (respect for persons), and should be used only if self-consent alone would bias the patient population. Methods: We analyzed acute stroke patients enrolled within 2h of symptom onset in the NIH Phase 3 Field Administration of Stroke Therapy - Magnesium (FAST-MAG) trial, comparing entry characteristics and outcomes with different consent mechanisms. Results: Among 1700 patients, median time from onset to study entry was 45 min (IQR 35-62). Overall, 60% of patients were competent and provided self-consent, 39% noncompetent and enrolled by proxy consent from an on-scene LAR, and 1% noncompetent enrolled using EFIC/delayed consent. Compared to self-consented patients, proxy-consented patients were: older, 73.8 vs 66.5, p&lt;0.001; more often female, 47% vs 40%, p&lt;0.02; and a higher frequency of several vascular risk factors, including hypertension, 81% vs 76%, p&lt;0.05, diabetes, 26% vs20%, p&lt;0.01, atrial fibrillation, 29% vs 17%, p&lt;0.001, and coronary artery disease, 24% vs 19%, p&lt;0.01. Proxy consent patients had more severe initial stroke deficits, prehospital LAMS, 4.1 vs 3.5, p&lt;0.001. Proxy consent patients with acute cerebral ischemia had more advanced initial ischemic stroke lesions, ASPECTS 8.3 vs 9.3, p&lt;0.001, and received tPA more often, 35% vs 20%, p&lt;0.001. Proxy consent patients with intracerebral hemorrhage patient had larger initial hemorrhage volume (cc), 42.2 vs 22.6, p&lt;0.001. Proxy consent patients had worse final outcomes, with freedom from disability (mRS 0-1) at 90d, 23.6% vs 44.3%, p&lt;0.001. Conclusions: Proxy-informed consent patients differ systematically from self-consent patients, with older age, more comorbidities, more severe deficits, and worse long term outcomes. To ensure that acute stroke trial cohorts are representative of the general stroke population, it is important that enrollment mechanisms include proxy and/or deferred consent.

Abstract TP41: Prevalence and Factors Associated with Early Ischemic Changes on Non-contrast CT Obtained Less Than 90 Minutes After Symptom Onset

Background: Usually early infarct signs on imaging take a few hours to develop in ischemic stroke. There may be a subset of patients manifesting early infarct signs on imaging hyperacutely. Objective: To determine the prevalence and factors associated with very early infarct signs on ASPECTS among patients with cerebral ischemia who were imaged &lt;90 minutes after symptom onset. Methods: Subjects participating in the NIH Field Administration of Stroke Therapy- Magnesium (FAST-MAG) phase 3 clinical trial with a final diagnosis of cerebral ischemia (TIA or Stroke) and initial imaging performed &lt;90 minutes from last known well time (LKWT) were included. ASPECTS was graded by a neuroradiologist (JPV) blinded to all clinical information. Individual subjects were characterized as having no early ischemic changes (ASPECTS 10) vs. early ischemic changes (ASPECTS 0-9). We describe the prevalence of early ischemic signs in this prospectively enrolled cohort, clinical factors associated with early ischemic changes as well as outcomes. Results: There were 566 cases imaged a mean of 71 (SD 11) minutes after LKWT. Mean age was 69 (SD 13), 43% women, 93% ischemic stroke, 7% TIA, median emergency department NIHSS 8 (IQR 3-16), median ASPECTS score of 10 (IQR 7-10, range 1-10). There were 200 cases with early ischemic findings (35%). Early ischemic changes were not related to age, blood pressure, history of hypertension, diabetes, dyslipidemia, coronary artery disease, or time to imaging (71 vs. 71 mins). Early ischemic changes were more commonly noted in women (50% vs. 39%, p=0.015) and associated higher presenting NIHSS (14 [IQR 7-20] vs 5 [IQR 2-11], p&lt;0.001). The presence of any hyperacute ischemia change was associate with worse 90-day outcome (modified Rankin score 3 [IQR 1-5] vs 1 [IQR 0-3, p&lt;0.001). Conclusions: Early ischemic changes were noted on about 1/3 rd of imaging obtained &lt;90 minutes after symptom onset. The presence of hyperacute ischemic changes is associated with more severe stroke and poor clinical outcomes.

Characteristics and Outcomes of Very Elderly Enrolled in a Prehospital Stroke Research Study

Greater numbers of individuals aged ≥80 years enjoy a high quality of life, yet historically stroke trials have excluded this population. We aimed to describe a population of very elderly successfully enrolled into an acute stroke trial and compare their characteristics and outcomes with the younger cohort. We analyzed consecutive patients enrolled <2 hours of symptom onset in a prehospital stroke treatment trial, the FAST-MAG clinical trial (Field Administration of Stroke Therapy-Magnesium). We gathered demographic, treatment, and outcome data for nonelderly (<80 years old), very elderly (≥80 years old), and extreme elderly (≥90 years old). We describe key differences in the population of elderly and the impact of their inclusion on the clinical trial. Of 1700 participants in FAST-MAG, there were 1210 nonelderly, 490 very elderly, and 60 extreme elderly subjects. Very elderly stroke patients successfully enrolled in a research study were more likely to be women, white, and have an ischemic mechanism rather than an intracerebral hemorrhage. Although the very elderly had generally poorer outcomes, 4 in 10 were functionally independent at 90 days. Inclusion of the very elderly population in acute stroke clinical trials would both significantly increase study participation and generalizability of future acute stroke clinical trials. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

Abstract 78: Pre-hospital Rapid Neurological Improvement in Acute Stroke Syndromes: Frequency and Clinical Outcomes

Introduction: There are no systematic data evaluating frequency and clinical outcome of patients with acute stroke syndromes presenting with rapid neurological improvement (RNI) in the pre-hospital setting. Our objectives were to determine frequency, magnitude, and clinical outcomes of RNI vs no-RNI. Hypothesis: Pre-hospital RNI predicts favorable clinical outcome as compared to no-RNI in acute stroke syndromes. Methods: Post-hoc analysis of The Field Administration of Stroke Therapy-Magnesium (FAST-MAG), a phase 3, randomized, double-blind, placebo-controlled clinical trial. Any-RNI was defined as a decrease of 2 or more points from the pre-hospital Los Angeles Motor Scale (PH-LAMS) to the hospital LAMS (H-LAMS), while dramatic-RNI was defined as a decrease of at least 4 points. Outcomes were: excellent recovery at 90 days (0-1 mRS), discharge disposition (home vs. not home), and death. Results: In the overall cohort of 1,700 subjects in FAST-MAG, frequency of any-RNI was 326 (19%), dramatic-RNI 98 (6%) and no-RNI 1,276 (75%). Mean age 71.4 (+/-13.2 SD), 67.1 (+/-13.3) and 69.1 (+/-13.6) for any-RNI, dramatic-RNI and no-RNI, respectively (p= 0.004). There was no gender difference across the 3 groups (p= 0.204). Hypertension (p=0.008) and diabetes (p= 0.014) were significantly less frequent among any-RNI and dramatic-RNI vs no-RNI. PH-LAMS medians: any-RNI: 3 (IQR 3-5), dramatic-RNI: 5 (4-5) and no-RNI: 4 (3-5), (p&lt;.0001). Median hospital NIHSS was: any-RNI 3 (1-6), dramatic-RNI 0 (0-2) vs no-RNI 12 (6-20) (p&lt;.0001). Any-RNI and dramatic-RNI were more likely to be discharged home (53% and 64%, respectively) vs no-RNI (25%) (p&lt;.0001). Any-RNI (61%) was more likely to have excellent outcome vs no-RNI (28%) (p&lt;0.0001) and after adjusting for covariates, the OR was 1.33 (95%CI 1.00-1.76, p=0.046). Conclusions: Frequency of pre-hospital any-RNI in the FAST-MAG cohort was almost 1 in 5 subjects, with 6% having dramatic recovery. While clinical outcomes were overall more favorable for acute stroke syndromes presenting with RNI, 47% (any-RNI) and 36% (dramatic-RNI) were not discharged home. Our data suggest that RNI in the pre-hospital setting does not always translate to favorable outcome. Factors affecting outcome in RNI need to be further explored.

Abstract TP366: National Institutes of Health Stroke Scale (NIHSS) is a Potent Predictor of Outcome in Acute Intracerebral Hemorrhage

Background: Although the NIHSS is a well-validated tool in assessing neurological deficit and predicting long-term outcome in acute cerebral ischemia, its utility in ICH has not been extensively studied. As NIHSS is routinely obtained in cases of stroke prior to imaging, it is often available in ICH patients to potentially assist physicians in triage, prognostication, and risk-adjustment. Methods: We analyzed consecutive patients enrolled in the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) phase 3 trial whose final diagnosis was ICH. Trained study nurses performed the NIHSS in the Emergency Department (ED) shortly after arrival and the modified Rankin Scale (mRS) at 90 days. Primary outcomes were disability or death (mRS 3-6) and mortality. Candidate potential predictor variables, including NIHSS, ICH Score, and GCS, those with threshold of p&lt;0.10 were candidate parameters for backward selection logistic regression to determine independent predictors of disability or death and of mortality. Results: Among the 384 ICH patients, age was mean 65 (±13); female 34%; race white 78%, black 10%, Asian 10%; Hispanic ethnicity 33%; and history of hypertension 78%. The ED NIHSS and GCS was performed a median 148 minutes (IQR 121-180) after last known well. Initial NIHSS was median 16 (IQR 9-16), GCS 15 (IQR 10-15), and ICH Score 1(IQR 0-2). NIHSS correlated with ICH Score (r=0.780) and GCS (r=0.860). At 90 days, median mRS was 4 (IQR 2-6), disability or death (mRS 3-6) was present in 70%, and mortality occurred in 26%. In predicting disability or death at 90 days, c statistics were: NIHSS 0.81, ICH Score 0.81, and GCS 0.72. NIHSS≥14 showed 72% sensitivity and 75% specificity. For mortality by 90 days, c statistics were: NIHSS 0.78, ICH Score 0.80, and GCS 0.73. NIHSS≥19 had 80% sensitivity and 70% specificity. On multivariate analysis age (OR 1.07, 95%CI 1.04-2.0) and NIHSS (OR 1.18, 95%CI 1.13-1.23) were independent predictors of disability and death. Conclusions: The initial NIHSS is a strong predictor of disability and death and good predictor of mortality after intracerebral hemorrhage, performing as well as the ICH Score and better than the GCS. Consideration should be given to routine performance and documentation of the NIHSS in ICH patients.