Characteristics and Outcomes of Patients who Refuse Intravenous Thrombolysis for Acute Ischemic Stroke - The San Diego Experience.

PURPOSE: Intravenous Thrombolysis (IV rt-PA) is administered in <10% of ischemic stroke patients. In rare cases, patients or caregivers refuse IV rt-PA treatment even when recommended by stroke practitioners. We sought to assess the characteristics and outcomes of patients who refuse IV rt-PA for acute ischemic stroke, and to compare outcomes between those who were treated with IV rt-PA and those who refused. METHODS: We examined data from the prospectively collected, IRB approved UC San Diego Stroke Registry who presented as a "stroke code" from July 2004 to July 2019 at two academic facilities and five community hospitals. Patients were included if they presented within 4.5 hours of symptom onset or last seen normal, had a "stroke code" alert activated, and were either treated with IV rt-PA or the reason for exclusion was patient/family refusal. Patients were considered "refusers" if IV rt-PA was recommended by the provider during the stroke code and the patient and/or legally authorized representative declined treatment. Baseline demographics, baseline National Institutes of Health Stroke Scale (NIHSS), treatment times and 90-day Modified Rankin Scale (mRS) were collected. Patients who refused IV rt-PA were compared to those that were treated with IV rt-PA. Data was examined for frequencies and distribution. Chi squared was used to evaluate nominal variables. Continuous variables were assessed by Pearson correlation and t test. Kruskal-Wallis or ANOVA were used to evaluate group differences. RESULTS: A total of 1056 patients were included in the analysis. Forty-seven patients (4.5%) refused IV rt-PA. There were no significant socio-demographic differences between patients who were treated with IV rt-PA and those who refused. Compared to patients who were treated with IV rt-PA, patients who refused IV rt-PA had a significantly lower baseline NIHSS (4 vs 9, p < 0.0001) and higher baseline mRS (IQR 0-1.0 vs 0-2.8, p < 0.001). The time from arrival to treatment decision was significantly longer in patients who refused IV rt-PA (group mean 57.9 min vs 48.8 min, p = 0.03). Data for 90-day outcome was available for 556 (55.1%) patients treated with IV rt-PA and 20 (42.5%) patients who refused IV rt-PA. There was no difference in 90-day mRS between groups (p = 0.68). CONCLUSIONS: There is a low rate of IV rt-PA refusal in our registry population which is similar to what previous studies have shown. We found that patients who refuse IV rt-PA have significantly milder deficits and significantly worse pre-morbid disability. We speculate that the longer "arrival to decision" time in the refuse IV rt-PA group is due to longer informed consent discussions. This analysis furthers the body of literature regarding rt-PA refusals.

A Stroke Care Model at an Academic, Comprehensive Stroke Center During the 2020 COVID-19 Pandemic.

BACKGROUND AND PURPOSE: The COVID-19 pandemic has required the adaptation of hyperacute stroke care (including stroke code pathways) and hospital stroke management. There remains a need to provide rapid and comprehensive assessment to acute stroke patients while reducing the risk of COVID-19 exposure, protecting healthcare providers, and preserving personal protective equipment (PPE) supplies. While the COVID infection is typically not a primary cerebrovascular condition, the downstream effects of this pandemic force adjustments to stroke care pathways to maintain optimal stroke patient outcomes. METHODS: The University of California San Diego (UCSD) Health System encompasses two academic, Comprehensive Stroke Centers (CSCs). The UCSD Stroke Center reviewed the national COVID-19 crisis and implications on stroke care. All current resources for stroke care were identified and adapted to include COVID-19 screening. The adjusted model focused on comprehensive and rapid acute stroke treatment, reduction of exposure to the healthcare team, and preservation of PPE. AIMS: The adjusted pathways implement telestroke assessments as a specific option for all inpatient and outpatient encounters and accounts for when telemedicine systems are not available or functional. COVID screening is done on all stroke patients. We outline a model of hyperacute stroke evaluation in an adapted stroke code protocol and novel methods of stroke patient management. CONCLUSIONS: The overall goal of the model is to preserve patient access and outcomes while decreasing potential COVID-19 exposure to patients and healthcare providers. This model also serves to reduce the use of vital PPE. It is critical that stroke providers share best practices via academic and vetted social media platforms for rapid dissemination of tools and care models during the COVID-19 crisis.

PREMISE: Posterior Circulation Results Comparing Embolectomy to Medical Intervention in Stroke Emergencies.

Background Intravenous (IV) tissue plasminogen activator (rt-PA) is a proven therapy for stroke in the acute treatment window. Recent published data has shown efficacy for embolectomy for acute ischemic strokes within up to six, 16 and 24 hours in the anterior circulation but there is no guideline for optimal therapy for patients with posterior circulation stroke, specifically basilar artery occlusion (BAO) outside the standard IV rt-PA treatment window. Aim To evaluate differences in outcomes between maximal medical treatment versus thrombectomy in BAO. Method We retrospectively evaluated prospectively collected acute stroke code patients from our stroke registry from 7/2004 to 7/2016. Patients who received IV rt-PA were excluded. Patients with evidence of posterior circulation ischemia and a hyper dense artery sign on initial non-contrast CT were included as a surrogate for direct vessel data before 2014. Patients after 9/2014 were selected by evidence of BAO on vessel imaging. All patients were categorized either as endovascular therapy or standard medical treatment alone. Demographics, hospital discharge location and Modified Rankin Scale (mRS) at 90 days were compared. Two-sample t-test and Fisher's exact test compared continuous and categorical variables across groups respectively. Results A total of 18 patients were included (three embolectomy and 15 medical therapy only). There were no significant differences in demographic data (age, gender, race, ethnicity, blood pressure, diabetes mellitus, hypertension, atrial fibrillation, tobacco use, alcohol use and initial NIHSS). Results for outcome and efficacies showed no statistical difference between medical management and endovascular intervention for functional outcome mRS (0-3) at 90 days (p = 0.2) and discharge location of home/inpatient rehabilitation vs other locations (p = 0.52). Conclusions Our single-center review showed the expected transition from predominantly medically treated posterior circulation BAOs, to a mixed pattern including embolectomy. Although the sample size was small, this study also illustrates the lack of clear efficacy data for optimal treatment strategies, and the ongoing treatment challenges in posterior circulation stroke population in a population of patients outside the rt-PA window.

Timing of symptomatic intracerebral hemorrhage after rt-PA treatment in ischemic stroke.

BACKGROUND: We investigated patterns in the time from recombinant tissue-type plasminogen activator (rt-PA) treatment to symptomatic intracranial hemorrhage (sICH) onset in acute ischemic stroke. METHODS: We retrospectively reviewed all admitted "stroke code" patients from 2003 to 2017 at the University of California San Diego Medical Center from a prospective stroke registry. We selected patients that received IV rt-PA within 4.5 hours after onset/last known well and had sICH prehospital discharge. sICH diagnosis was made by prospective review. Endovascular-treated patients were excluded, given the variability of practice. sICH was prospectively defined as any new radiographic (CT/MRI) hemorrhage after rt-PA treatment and any worsened neurologic examination. Time to sICH was the time from rt-PA administration start to documented STAT head CT order time with the first evidence of new hemorrhage. Charts were reviewed for examination time metrics, demographics, clinical history, and neuroimaging. RESULTS: sICH was identified in 28 rt-PA-only treated patients. The mean time to sICH was 18.28 hours (range 2.4-34 hours). Median time to sICH was 18.25 hours. sICH was correlated with increased age (p = 0.02) and increased NIH Stroke Scale (p = 0.01). CONCLUSIONS: Our findings suggest that rt-PA patients have the highest risk of post rt-PA sICH within the first 24 hours after treatment. This supports monitoring of rt-PA-treated patients in specialized settings such as neuro-intensive care units or stroke units. Our findings suggest that the probability of sICH is low 36 hours post rt-PA. Future larger studies are warranted to identify the patterns of bleeding after rt-PA administration.

Mapping a Reliable Stroke Onset Time Course Using Signal Intensity on DWI Scans.

BACKGROUND AND PURPOSE: Identifying a last known well (LKW) time surrogate for acute stroke is vital to increase stroke treatment. Diffusion-weighted imaging (DWI) signal intensity initially increases from onset of stroke but mapping a reliable time course to the signal intensity has not been demonstrated. METHODS: We retrospectively reviewed stroke code patients between 1/2016 and 6/2017 from the prospective; Institutional review board (IRB) approved University of California San Diego Stroke Registry. Patients who had magnetic resonance imaging of brain from onset, with or without intervention, are included. All ischemic strokes were confirmed and timing from onset to imaging was calculated. Raw DWI intensity is measured using IMPAX software and compared to contralateral side for control for a relative DWI intensity (rDWI). LKW and magnetic resonance imaging (MRI) time were collected by chart review. Correlation is assessed using Pearson correlation coefficient between DWI intensity, rDWI, and time to MRI imaging. 1.5T, 3T, and combined modalities were examined. RESULTS: Seventy-eight patients were included in this analysis. Overall, there was statistically significant positive correlation (.53, P < .001) between DWI intensity and LKW time irrespective of scanner strength. Using 1.5T analyses, there was good correlation (.46, P < .001). 3T MRI analysis further showed comparatively stronger positive correlation (.66, P < .001). CONCLUSIONS: There is good correlation between DWI intensity and minutes from onset to MRI. This suggests a time-dependent DWI intensity response and supports the potential use of DWI intensity measurements to extrapolate an LKW time. Further studies are being pursued to increase both experience and generalizability.

The Sustained DeyeCOM Sign as a Predictor of Large Vessel Occlusions and Stroke Mimics.

INTRODUCTION: Rapid imaging in acute stroke is critical and often occurs before full examination. Early, reliable examination findings clarify diagnosis and improve treatment times. The DeyeCOM sign has been described as a predictor of ischemic stroke. In this study, we evaluate a sustained DeyeCOM sign on serial computed tomography scans in prediction of large vessel occlusion. METHODS: Between April and June 2017, we retrospectively reviewed 46 patients with acute stroke from the University of California, San Diego Stroke Registry, who had both computed tomography and computed tomography angiography as part of their acute work-up. A DeyeCOM(+) sign was defined as a conjugate gaze deviation on imaging of at least 15°. DeyeCOM(++) was defined as sustained gaze deviation on both scans. RESULTS: Three groups of patients were observed: DeyeCOM(++), nonsustained gaze deviation, and no gaze deviation (DeyeCOM(--)). All patients in the DeyeCOM(++) (8 of 8, 100%) had large vessel occlusion. Of those with nonsustained gaze deviation, 2 of 7 (29%) had large vessel occlusion. No patients in the DeyeCOM(--) (0 of 31, 100%) had large vessel occlusion. The specificity and sensitivity of DeyeCOM(++) for large vessel occlusion was 100% (confidence interval [CI] .90-1.0) and 80% (CI .44-.97). The specificity and sensitivity of DeyeCOM(--) for absence of large vessel occlusion was 100% (CI .69-1.0) and 86% (CI .70-.95). CONCLUSIONS: DeyeCOM(++) had 100% specificity for large vessel occlusion, whereas DeyeCOM(--) had a 100% specificity for absence of large vessel occlusion. Sustained DeyeCOM, whether positive or negative, is a strong predictor of ultimate diagnosis that could lead to quicker endovascular treatment times.

Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2).

BACKGROUND AND PURPOSE: Therapeutic hypothermia is a potent neuroprotectant approved for cerebral protection after neonatal hypoxia-ischemia and cardiac arrest. Therapeutic hypothermia for acute ischemic stroke is safe and feasible in pilot trials. We designed a study protocol to provide safer, faster therapeutic hypothermia in stroke patients. METHODS: Safety procedures and 4°C saline infusions for faster cooling were added to the ICTuS trial (Intravascular Cooling in the Treatment of Stroke) protocol. A femoral venous intravascular cooling catheter after intravenous recombinant tissue-type plasminogen activator in eligible patients provided 24 hours cooling followed by a 12-hour rewarm. Serial safety assessments and imaging were performed. The primary end point was 3-month modified Rankin score 0,1. RESULTS: Of the intended 1600 subjects, 120 were enrolled before the study was stopped. Randomly, 63 were to receive hypothermia plus antishivering treatment and 57 normothermia. Compared with previous studies, cooling rates were improved with a cold saline bolus, without fluid overload. The intention-to-treat primary outcome of 90-day modified Rankin Score 0,1 occurred in 33% hypothermia and 38% normothermia subjects, odds ratio (95% confidence interval) of 0.81 (0.36-1.85). Serious adverse events occurred equally. Mortality was 15.9% hypothermia and 8.8% normothermia subjects, odds ratio (95% confidence interval) of 1.95 (0.56-7.79). Pneumonia occurred in 19% hypothermia versus 10.5% in normothermia subjects, odds ratio (95% confidence interval) of 1.99 (0.63-6.98). CONCLUSIONS: Intravascular therapeutic hypothermia was confirmed to be safe and feasible in recombinant tissue-type plasminogen activator-treated acute ischemic stroke patients. Protocol changes designed to reduce pneumonia risk appeared to fail, although the sample is small. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01123161.

Feasibility and Safety of Using External Counterpulsation to Augment Cerebral Blood Flow in Acute Ischemic Stroke-The Counterpulsation to Upgrade Forward Flow in Stroke (CUFFS) Trial.

BACKGROUND: External counterpulsation (ECP) increases perfusion to a variety of organs and may be helpful for acute stroke. METHODS: We conducted a single-blinded, prospective, randomized controlled feasibility and safety trial of ECP for acute middle cerebral artery (MCA) ischemic stroke. Twenty-three patients presenting within 48 hours of symptom onset were randomized into one of two groups. One group was treated with ECP for 1 hour at a pressure of up to 300 mmHg ("full pressure"). During the procedure, we also determined the highest possible pressure that would augment MCA mean flow velocity (MFV) by 15%. The other group was treated with ECP at 75 mmHg ("sham pressure"). Transcranial Doppler MCA flow velocities and National Institutes of Health Stroke Scale (NIHSS) scores of both groups were checked before, during, and after ECP. Outcomes were assessed at 30 days after randomization. RESULTS: Although the procedures were feasible to implement, there was a frequent inability to augment MFV by 15% despite maximal pressures in full-pressure patients. In sham-pressure patients, however, MFV frequently increased as shown by increases in peak systolic velocity and end diastolic velocity. In both groups, starting ECP was often associated with contemporaneous improvements in NIHSS stroke scores. There were no between-group differences in NIHSS, modified Rankin Scale Scores, and Barthel Indices, and no device or treatment-related serious adverse events, deaths, intracerebral hemorrhages, or episodes of acute neuro-worsening. CONCLUSIONS: ECP was safe and feasible to use in patients with acute ischemic stroke. It was associated with unexpected effects on flow velocity, and contemporaneous improvements in NIHSS score regardless of pressure used, with a possibility that even very low ECP pressures had an effect. Further study is warranted.

The "DeyeCOM Sign": Predictive Value in Acute Stroke Code Evaluations.

BACKGROUND: Rapid diagnosis in stroke is critical. Computed tomography is often performed initially, even before a neurologic examination. Gaze deviation has been correlated with stroke diagnosis in some cohorts. Conjugate gaze deviation on stroke code imaging, the "DeyeCOM sign," may have emergency stroke care implications. METHODS: We evaluated stroke code imaging from the University of California, San Diego database (2007-2013) for "DeyeCOM sign" diagnostic and predictive utility. Patients were grouped as DeyeCOM+ if conjugate gaze deviation was noted. The differences were assessed using the Fisher exact test for categorical and the Wilcoxon rank-sum test for continuous variables. RESULTS: We evaluated 342 patients; 106 (31%) were DeyeCOM+. Mean age was 63. The most common diagnoses in the DeyeCOM+ group were ischemic stroke (50.94%), transient ischemic attack (8.49%), other (8.49%), somatization (6.6%), and hemorrhage (5.66%). The National Institutes of Health Stroke Scale was greater in stroke patients than that in nonstroke (8.2 versus 3.8; P < .0001), and in DeyeCOM+ compared with DeyeCOM- (6.8 versus 5.6; P = .03). DeyeCOM+ patients were more likely to have a +gaze score (26.4% versus 9.8%; P < .0001), and +gaze patients were more likely to have final stroke diagnosis (26.0% versus 3.6%; P < .0001). There was no overall difference between groups in final stroke diagnosis; however, patients with deviation of 15° or more were more likely to have final diagnosis stroke (63.9% versus 47.9%; P = .03). CONCLUSIONS: DeyeCOM+ patients scored higher and were more likely to have +gaze on the stroke scale, and deviation of 15° or more was correlated with final diagnosis stroke. In current environments, there is pressure to complete stroke evaluations rapidly. Reliable imaging information obtained early (such as gaze deviation on scan correlating with scale score and final stroke diagnosis) could augment decision making even with negative imaging.

Endovascular therapeutic hypothermia for acute ischemic stroke: ICTuS 2/3 protocol.

Therapeutic hypothermia improves neurological outcome after out-of-hospital cardiac arrest or neonatal hypoxic-ischemic injury. Although supported by preclinical evidence, therapeutic hypothermia for acute stroke remains under study. In the Intravascular Cooling in the Treatment of Stroke (ICTuS) trial, awake stroke patients were successfully cooled using an endovascular cooling catheter and a novel antishivering regimen. In the ICTuS-L study, the combination of endovascular hypothermia and thrombolysis proved feasible; while hypothermia was associated with no increased risk of bleeding complications, there was an increased association with pneumonia. Despite efforts to expedite, cooling began on average six-hours after stroke onset. We designed a novel Phase 2/3 trial to further test the safety of combined thrombolysis and endovascular hypothermia and to determine if the combination shows superiority compared with thrombolysis alone. ICTuS 2 (n = 400) will assess four hypotheses, and if milestones are met, ICTuS 3 (n = 1200) will begin as a seamless continuation for a total sample of 1600 patients. The ICTuS 2 milestones include (1) target temperature reached within six-hours of symptom onset; (2) no increased risk of pneumonia; (3) no increase in signs/symptoms of fluid overload due to chilled saline infusions; and (4) sufficient recruitment to complete the trial on time. The ICTuS 2/3 protocol contains novel features - based on the previous ICTuS and ICTuS-L trials - designed to achieve these milestones. Innovations include scrupulous pneumonia surveillance, intravenous chilled saline immediately after randomization to induce rapid cooling, and a requirement for catheter placement within two-hours of thrombolysis. An Investigational Device Exemption has been obtained and an initial group of sites initiated.

Does symptom onset to primary stroke center time goals affect stroke outcome?

BACKGROUND: Treating acute ischemic stroke (AIS) within 4.5 hours and door-to-needle time of less than 60 minutes may optimize recovery. It is unknown if onset to Primary Stroke Center (PSC) time goals affect outcome. The purpose of this study was to examine effects of symptom onset to PSC time goals on outcome. METHODS: Analysis included prospectively collected data from the University of California San Diego Specialized Program of Treatment Research in Acute Stroke. All AIS patients treated with intravenous recombinant tissue plasminogen activator were included if treated within 270 minutes, and 90-day modified Rankin Scale (mRS) score was known. Primary outcome of the 90-day mRS was analyzed using multivariable logistic regression. Good outcome was defined as a 90-day mRS score of 0-2. Variables assessed were time from onset to arrival, stroke code, neurologic exam, imaging, laboratories, treatment decision, and treatment (by quartiles). RESULTS: Two hundred ninety-one patients were included (49.8% female, mean age 70.6 ± 16.1, median National Institutes of Health Stroke Scale 10, SD = 8.5). Good outcome occurred in 45% of patients. Significant baseline differences included HTN (P ≤ .001), A fib (P ≤ .001), prestroke mRS (P < .001), and Hispanic ethnicity (P = .011). Comparing good with poor outcome groups: mean onset to arrival was 70.6 min versus 62.5 min (P = .129) and mean onset to treatment was 140.1 min versus 134.9 min (P = .118). Controlling for prespecified covariates, no PSC time goals were significant predictors of the 90-day outcome. CONCLUSIONS: In our Comprehensive Stroke Center (CSC), onset to PSC time goals were not significant predictors of the 90-day outcome. Expedited care processes in CSC may compensate for differences in outcome. These results should be validated in a larger cohort and in PSCs versus CSCs.

Transcranial laser therapy for acute ischemic stroke: a pooled analysis of NEST-1 and NEST-2.

BACKGROUND: NeuroThera Effectiveness and Safety Trials (NEST) 1 and 2 have demonstrated safety of transcranial laser therapy (TLT) for human treatment in acute ischemic stroke. NEST 1 study suggested efficacy of TLT but the following NEST 2, despite strong signals, missed reaching significance on its primary efficacy endpoint. In order to assess efficacy in a larger cohort, a pooled analysis was therefore performed. METHODS: The two studies were first compared for heterogeneity, and then a pooled analysis was performed to assess overall safety and efficacy, and examined particular subgroups. The primary endpoint for the pooled analysis was dichotomized modified Rankin scale (mRS) 0-2 at 90 days. RESULTS: Efficacy analysis for the intention-to-treat population was based on a total of 778 patients. Baseline characteristics and prognostic factors were balanced between the two groups. The TLT group (n = 410) success rate measured by the dichotomized 90-day mRS was significantly higher compared with the sham group (n = 368) (P = 0·003, OR: 1·67, 95% CI: 1·19-2·35). The distribution of scores on the 90-day mRS was significantly different in TLT compared with sham (P = 0·0005 Cochran-Mantel-Haenszel). Subgroup analysis identified moderate strokes as a predictor of better treatment response. CONCLUSIONS: This pooled analysis support the likelihood that transcranial laser therapy is effective for the treatment of acute ischemic stroke when initiated within 24 h of stroke onset. If ultimately confirmed, transcranial laser therapy will change management and improve outcomes of far more patients with acute ischemic stroke.

Determinants of effective cooling during endovascular hypothermia.

BACKGROUND: Therapeutic hypothermia is a promising neuroprotective therapy with multiple mechanisms of action. We demonstrated the feasibility of thrombolysis combined with endovascular hypothermia, but not all patients achieved effective cooling. We sought to identify the factors that determined effective cooling. METHODS: In 26 patients who underwent endovascular hypothermia, we computed four measures of effective cooling: time to reach target; Area-Under-the-Curve (AUC) 34 ratio; AUC-34; and AUC-35. By multivariate regression, we examined the effects of age, weight, starting temperature, body mass index, body surface area (BSA), gender, shivering, and total meperidine dose on the four outcome measures. RESULTS: In univariate analyses, all four outcome measures were significantly influenced by BSA (p < 0.01 in all univariate analyses). Time to reach target temperature was quicker in older patients (p < 0.01). Shivering and meperidine dose were highly intercorrelated (r = 0.6, p < 0.01) and both marginally influenced all four outcome measures. In multivariate analysis, AUC ratio and time to reach target temperature were significantly influenced by BSA (p < 0.01) and meperidine (p < 0.05); AUC-34 was influenced only by BSA (p < 0.01). The AUC-35 was influenced by BSA (p < 0.01), shivering, and total meperidine dose (p < 0.05). CONCLUSIONS: The most important determinant of effective cooling during endovascular hypothermia is BSA; larger patients are more difficult to cool and maintain in therapeutic range. Older patients cool more quickly. Shivering was well controlled by the combination of meperidine, buspirone, and surface counter-warming and only minimally influenced cooling effectiveness. Future trials of therapeutic hypothermia may include added measures to cool larger patients more effectively.

Late night activity regarding stroke codes: LuNAR strokes.

BACKGROUND: There is diurnal variation for cardiac arrest and sudden cardiac death. Stroke may show a similar pattern. We assessed whether strokes presenting during a particular time of day or night are more likely of vascular etiology. AIM: To compare emergency department stroke codes arriving between 22:00 and 8:00 hours (LuNAR strokes) vs. others (n-LuNAR strokes). The purpose was to determine if late night strokes are more likely to be true strokes or warrant acute tissue plasminogen activator evaluations. METHODS: We reviewed prospectively collected cases in the University of California, San Diego Stroke Team database gathered over a four-year period. Stroke codes at six emergency departments were classified based on arrival time. Those arriving between 22:00 and 8:00 hours were classified as LuNAR stroke codes, the remainder were classified as 'n-LuNAR'. Patients were further classified as intracerebral hemorrhage, acute ischemic stroke not receiving tissue plasminogen activator, acute ischemic stroke receiving tissue plasminogen activator, transient ischemic attack, and nonstroke. Categorical outcomes were compared using Fisher's Exact test. Continuous outcomes were compared using Wilcoxon's Rank-sum test. RESULTS: A total of 1607 patients were included in our study, of which, 299 (19%) were LuNAR code strokes. The overall median NIHSS was five, higher in the LuNAR group (n-LuNAR 5, LuNAR 7; P=0·022). There was no overall differences in patient diagnoses between LuNAR and n-LuNAR strokes (P=0·169) or diagnosis of acute ischemic stroke receiving tissue plasminogen activator (n-LuNAR 191 (14·6%), LuNAR 42 (14·0%); P=0·86). Mean arrival to computed tomography scan time was longer during LuNAR hours (n-LuNAR 54·9±76·3 min, LuNAR 62·5±87·7 min; P=0·027). There was no significant difference in 90-day mortality (n-LuNAR 15·0%, LuNAR 13·2%; P=0·45). CONCLUSIONS: Our stroke center experience showed no difference in diagnosis of acute ischemic stroke between day and night stroke codes. This similarity was further supported in similar rates of tissue plasminogen activator administration. Late night strokes may warrant a more rapid stroke specialist evaluation due to the longer time elapsed from symptom onset and the longer time to computed tomography scan.

Therapeutic hypothermia is associated with a decrease in urine output in acute stroke patients.

AIMS: It is unclear what effect therapeutic hypothermia may have on renal function, because its effect has so far been primarily evaluated in settings in which there may be possible confounding perturbations in cardiovascular and renal physiology, such deep intraoperative hypothermia, general anesthesia, and post-cardiac arrest. We sought to determine if therapeutic hypothermia affects renal function in awake patients with normal renal function who were enrolled into a clinical trial of hypothermia plus intravenous thrombolysis for acute ischemic stroke. METHODS: Eleven patients with normal renal function were cooled to 33°C for 24 h using an endovascular catheter, and then re-warmed over 12 h to 36.5°C, while hourly temperature, blood pressure, and fluid status data was recorded. Blood samples for blood urea nitrogen (BUN), creatinine, and hematocrit were drawn prior to treatment (baseline), immediately after hypothermia and re-warming (day 2), and again at day 7 or discharge, and values compared. RESULTS: On initiation of cooling, temperatures dropped from a median pre-treatment value of 36.1°C (IQR: 35.8-36.4°C) to 33.1°C (IQR: 33.1-33.4°C). Urine output decreased 5.1 ml/h for every 1°C decrease in body temperature (p-value=0.001), with no associated serious adverse events. There were no statistically significant changes in BUN, creatinine, or hematocrit in the hypothermia patients. CONCLUSION: Inducing hypothermia in patients with relatively unperturbed renal physiology results in a decrease in urine output that is linearly correlated with the decrease in core temperature. This has important implications for fluid management in patients undergoing therapeutic hypothermia.

Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results.

BACKGROUND AND PURPOSE: Induced hypothermia is a promising neuroprotective therapy. We studied the feasibility and safety of hypothermia and thrombolysis after acute ischemic stroke. METHODS: Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke (ICTuS-L) was a randomized, multicenter trial of hypothermia and intravenous tissue plasminogen activator in patients treated within 6 hours after ischemic stroke. Enrollment was stratified to the treatment time windows 0 to 3 and 3 to 6 hours. Patients presenting within 3 hours of symptom onset received standard dose intravenous alteplase and were randomized to undergo 24 hours of endovascular cooling to 33°C followed by 12 hours of controlled rewarming or normothermia treatment. Patients presenting between 3 and 6 hours were randomized twice: to receive tissue plasminogen activator or not and to receive hypothermia or not. Results- In total, 59 patients were enrolled. One patient was enrolled but not treated when pneumonia was discovered just before treatment. All 44 patients enrolled within 3 hours and 4 of 14 patients enrolled between 3 to 6 hours received tissue plasminogen activator. Overall, 28 patients randomized to receive hypothermia (HY) and 30 to normothermia (NT). Baseline demographics and risk factors were similar between groups. Mean age was 65.5±12.1 years and baseline National Institutes of Health Stroke Scale score was 14.0±5.0; 32 (55%) were male. Cooling was achieved in all patients except 2 in whom there were technical difficulties. The median time to target temperature after catheter placement was 67 minutes (Quartile 1 57.3 to Quartile 3 99.4). At 3 months, 18% of patients treated with hypothermia had a modified Rankin Scale score of 0 or 1 versus 24% in the normothermia groups (nonsignificant). Symptomatic intracranial hemorrhage occurred in 4 patients (68); all were treated with tissue plasminogen activator <3 hours (1 received hypothermia). Six patients in the hypothermia and 5 in the normothermia groups died within 90 days (nonsignificant). Pneumonia occurred in 14 patients in the hypothermia and in 3 of the normothermia groups (P=0.001). The pneumonia rate did not significantly adversely affect 3 month modified Rankin Scale score (P=0.32). CONCLUSIONS: This study demonstrates the feasibility and preliminary safety of combining endovascular hypothermia after stroke with intravenous thrombolysis. Pneumonia was more frequent after hypothermia, but further studies are needed to determine its effect on patient outcome and whether it can be prevented. A definitive efficacy trial is necessary to evaluate the efficacy of therapeutic hypothermia for acute stroke.

An ethical hierarchy for decision making during medical emergencies.

Evidence from well-designed clinical trials may guide clinicians, reduce regional variation, and lead to improved outcomes. Many physicians choose to ignore evidence-based practice guidelines. Using unproven therapies outside of a randomized trial slows recruitment in clinical trials that could yield information on clinical and economic efficacy. Using acute stroke therapy as an illustration, we present an ethical hierarchy for therapeutic decision making during medical emergencies. First, physicians should offer standard care. If no standard care option exists, the physician should consider enrollment in a randomized clinical trial. If no trial is appropriate, the physician should consider a nonrandomized registry, or consensus-based guidelines. Finally, only after considering the first 3 options, the physician should use best judgment based on previous personal experience and any published case series or anecdotes. Given the paucity of quality randomized clinical trial data for most medical decisions, the "best judgment" option will be used most frequently. Nevertheless, such a hierarchy is needed because of the limited time during medical emergencies for consideration of general principles of clinical decision making. There should be general agreement in advance as to the hierarchy to follow in selecting treatment for critically ill patients. Were more clinicians to follow this hierarchy, and choose to participate in clinical trials, the generation of new knowledge would accelerate, yielding rigorous data supporting or refuting the efficacy and safety of new interventions more quickly, thus benefiting far more patients over time.

Analysis of the National Institute of Neurological Disorders and Stroke tissue plasminogen activator studies following European Cooperative Acute Stroke Study III patient selection criteria.

BACKGROUND: In 1995 two studies by the National Institute of Neurological Disorders and Stroke (NINDS) proved that intravenous tissue plasminogen activator (t-PA) was superior to placebo in patients with stroke of less than 3 hours' duration. The recently published European Cooperative Acute Stroke Study (ECASS) III introduced new patient selection criteria and treatment between 3 and 4.5 hours. Using these criteria, t-PA was shown effective at the later time window. Both analyses used the 3-month modified Rankin scale (mRS) score as main primary outcome. We sought to study the effect of applying the ECASS III selection criteria to the original NINDS cohort. METHODS: We analyzed the subgroup of patients from NINDS sample who matched the ECASSS III criteria. We examined 3-month outcomes adjusted and unadjusted for confounding factors. RESULTS: The NINDS t-PA study included 624 patients. A total of 200 in the t-PA-treated group and 199 in the placebo group were selected after applying ECASS III criteria. Of these selected patients, 52% in the t-PA group versus 31% had mRS score of 0 or 1 at 3 months (P < .001). The unadjusted odds ratio for t-PA treatment versus placebo on day-90 mRS score 0 to 1 versus 2 to 6 was 2.45 (95% confidence interval: 1.63-3.69). When adjusted for baseline National Institutes of Health Stroke Scale score, smoking status, time to treatment, and history of hypertension, the odds ratio was 2.14 (95% confidence interval: 1.34-3.41) (P < .001). CONCLUSION: Using the ECASS III criteria in patients treated in less than 3 hours, 52% of t-PA-treated patients had a favorable outcome at 3 months.

Effect of endovascular hypothermia on acute ischemic edema: morphometric analysis of the ICTuS trial.

INTRODUCTION: Pilot studies of hypothermia for stroke suggest a potential benefit in humans. We sought to test whether hypothermia decreases post-ischemic edema using CT scans from a pilot trial of endovascular hypothermia for stroke. METHODS: Eighteen patients with acute ischemic stroke underwent therapeutic hypothermia (target = 33 degrees C) for 12 or 24 h followed by a 12-h controlled re-warm using an endovascular system. CT scans obtained at baseline, 36-48 h (right after cooling and re-warming) and 30 days were digitized, intracranial compartment volumes measured using a validated stereological technique, and the calculated change in CSF volume between the three time-points were used as an estimate of edema formation in each patient. Patients were grouped retrospectively for analysis based on whether they cooled effectively (i.e., to a temperature nadir of less than 34.5 degrees C within 8 h) or not. RESULTS: Eleven patients were cooled partially or not at all, and seven were effectively cooled. Baseline demographics and compartment volumes and densities were similar in both groups. At 36-48 h, the total CSF volume had significantly decreased in the not-cooled group compared to the cooled group (P < 0.05), with no significant difference in mean volume of ischemia between them (73 +/- 73 ml vs. 54 +/- 59 ml, respectively), suggesting an ameliorative effect of hypothermia on acute edema formation. At 30 days, the difference in CSF volumes had resolved, and infarct volumes (73 +/- 71 ml vs. 84 +/- 102 ml, respectively) and functional outcomes were comparable. CONCLUSIONS: Endovascular hypothermia decreases acute post-ischemic cerebral edema. A larger trial is warranted to determine if it affects final infarct volume and outcome in stroke.