Karen Rapp

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). Conclusion— 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.

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.

Ultra-Rapid Identification, Triage, and Enrollment of Stroke Patients into Clinical Trials

Effective therapy for acute ischemic stroke will require very rapid evaluation of patients so that treatment can begin soon enough to salvage injured but viable brain. Limited data suggest that neurons in the ischemic penumbra survive for a few hours, at the most. It is critical to know whether our medical system can overcome the many practical obstacles to ultra-rapid recognition,, transport, and treatment of stroke patients. We analyzed our patient recruitment into clinical treatment trials over time, attempting to identify strategies that improved recruitment. Specifically, we studied whether the imposition of an ultra-short time limit for treatment initiation, 3 h from stroke onset, impaired recruitment Prior to adopting the strict time limit, we enrolled about 0.4 patients per month per participating hospital. After adopting the limit, we enrolled about 0.7 patients per month per hospital. Our data indicate that patient recruitment may be maintained and even increased despite a demanding time limit for treatment. The data also suggest that a very short time window of survivability of the ischemic penumbra should not discourage efforts to develop new methods of salvaging brain, for we have shown that the medical delivery system in one county can be modified to allow ultra-rapid patient recognition, evaluation, and treatment.

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.

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.

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.

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. ANN NEUROL 2010;67:434‐440

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 non-stroke. Categorical outcomes were compared using Fishers Exact test. Continuous outcomes were compared using Wilcoxons 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.

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.