Christiana E. Hall

New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies

Abstract Intracerebral hemorrhage (ICH) remains a major medical problem, for which there is no effective treatment. However, extensive experimental and clinical research carried out in recent years has brought to light new exciting ideas for novel potential treatments. First, it was well documented that the management of hypertension helps to prevent new and recurrent ICH. Also, development of new guidelines for management of hypertension after the onset of the ICH may help in more effective ICH treatment. Existing contemporary data collected from preclinical studies indicates that ICH–induced inflammation represents a key factor leading to secondary brain damage, suggesting that some anti–inflammatory approaches can be used to treat hemorrhagic stroke. In this article, beyond discussing implications related to hypertension, we will summarize important (but not all) new discoveries connecting the role of inflammation to ICH pathology. Selected aspects of inflammatory response including the role of cytokines, transcription factor nuclear factor–kB, microglia activation, astrogliosis, and complement activation will be introduced. We will also discuss the role for reactive oxygen species and metalloproteinases in ICH pathogenesis and introduce basic knowledge on the nature of ICH–induced cell death including apoptosis. Potential targets for intervention and translation will be discussed.

REACH Clinical Feasibility of a Rural Telestroke Network

Background and Purpose— Development of stroke networks is critical to bringing guideline-driven stroke care to rural, underserved areas. Methods— A Web-based telestroke tool, REACH, was developed to provide a foundation for a rural stroke network that delivered acute stroke consults 24 hours per day 7 days per week to 8 rural community hospitals in Georgia. Results— There were 194 acute stroke consults delivered. Thirty patients were treated with tissue plasminogen activator (tPA). The mean National Institutes of Health Stroke Score (NIHSS) was 15.4, and the median NIHSS was 12.5. The mean onset to treatment time (OTT) was 122 minutes. The OTT dropped from 143 minutes in the first 10 patients treated to 111 minutes in last 20 patients. Of the 30 patients treated with tPA, 23% (7) were treated in ≤90 minutes and 60% (18) were treated within 2 hours. There were no symptomatic intracerebral hemorrhages. Conclusions— The REACH telestroke system permits the rapid and safe use of tPA in rural community hospitals. Over time, the system became more efficient and OTT decreased.

Minocycline to Improve Neurologic Outcome in Stroke (MINOS): A dose-finding study

Background and Purpose— Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ischemic stroke. Methods— Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days. Results— Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65±13.7 years), race (83% white), and sex (47% female) were consistent across the doses. The mean baseline National Institutes of Health Stroke Scale score was 8.5±5.8 and 60% received tissue plasminogen activator. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10-mg/kg dose. No severe hemorrhages occurred in tissue plasminogen activator-treated patients. Pharmacokinetic analysis (n=22) revealed a half-life of approximately 24 hours and linearity of parameters over doses. Conclusions— Minocycline is safe and well tolerated up to doses of 10 mg/kg intravenously alone and in combination with tissue plasminogen activator. The half-life of minocycline is approximately 24 hours, allowing every 24-hour dosing. Minocycline may be an ideal agent to use with tissue plasminogen activator.

Glucose Regulation in Acute Stroke Patients (GRASP) Trial A Randomized Pilot Trial

Background and Purpose— Hyperglycemia is associated with worse outcome in patients with acute stroke. Methods— We conducted a prospective, randomized, multicenter, 3-arm trial (tight control [target 70 to 110 mg/dL], loose control [target 70 to 200 mg/dL], and control usual care [70 to 300 mg/dL]) to assess the feasibility and safety of 2 insulin infusion protocol targets in patients with acute ischemic stroke. The planned sample was 72 subjects. Results— A total of 74 subjects were enrolled. Seventy-two (97%) had data available for the primary analyses and 73 (99%) had 3-month clinical outcome data. Median age was 67 years, median National Institutes of Health Stroke Scale score was 8, median glucose was 163 mg/dL, and median time to randomization was 10.7 hours. Fifty-nine percent of patients were diabetic, 35% received thrombolysis, and 14% of subjects died within 3 months. The loose control and usual care groups had median glucose concentrations of 151 mg/dL. The tight control group had a median glucose concentration of 111 mg/dL. The loose control group spent 90% of the first 24 hours in target and the tight group 44% of time in target. There was only one symptomatic patient with hypoglycemia in the loose control group (4%) and zero in the tight control group. The overall rates of hypoglycemia (<55 mg/dL) were 4% in control, 4% in loose, and 30% in tight. Exploratory efficacy analysis was conducted. Conclusions— Insulin infusion for patients with acute ischemic stroke is feasible and safe using the insulin infusion protocol in the Glucose Regulation in Acute Stroke Patients (GRASP) trial. Exploratory efficacy analysis supports further comparative study.

Ischemic Stunning of the Brain: Early Recanalization Without Immediate Clinical Improvement in Acute Ischemic Stroke

Background and Purpose— Early arterial recanalization (ER) with intravenous tissue plasminogen activator (tPA) can lead to dramatic clinical recovery, whereas some patients do not experience immediate clinical improvement. Methods— Consecutive patients received tPA 0.9 mg/kg IV within 3 hours after symptom onset. All had M1 or M2 middle cerebral artery occlusions on pretreatment transcranial Doppler. Patients were continuously monitored for 2 hours after bolus. ER was defined as the Thrombolysis in Brain Ischemia intracranial flow increase by ≥1 grade. Stroke severity (National Institutes of Health Stroke Scale [NIHSS]) and recovery (modified Rankin Scale) were assessed independently of transcranial Doppler. Results— One hundred twenty patients (mean age, 68±15 years; 63 women; median NIHSS, 17; range, 5 to 29; 90% with ≥10 points) received tPA at a median of 120 minutes, 50% within the first 2 hours. ER was observed in 73 patients (32 complete, 41 partial). No immediate clinical changes (n=23) or worsening (by 1 to 6 points on NIHSS, n=4) was observed in 37% of ERs (nonresponders). Complete ER was found in 8 of these 27 patients. At 24 hours, 22 of 27 patients (82%) had persisting deficits of NIHSS ≥10 points, yet 37% of these nonresponders (10 of 27) still achieved good outcome (modified Rankin score, 0 to 2) at 3 months. Among nonresponders with good outcome, 100% had detectable residual flow signals, and 70% had compensatory flow diversion on prebolus transcranial Doppler compared with 65% and 29% of nonresponders with poor outcome (P <0.05). Compared with responders (n=46), nonresponders had similar prebolus median NIHSS of 16 to 17 points, bolus times of 120 to 132 minutes, median speed of thrombolysis (30 minutes), and ER times of 190 to 193 minutes after onset. Reocclusion occurred in 3 of 4 patients with clinical worsening, 30% of other nonresponders, and 22% of responders. Symptomatic hemorrhage rate was 4% in both groups. At 3 months, mortality was 33% in nonresponders compared with 9% in responders (P =0.001). Conclusions— After successful arterial ER with tPA therapy, lack of early clinical changes or worsening is relatively common (37%) and appears to be independent of time to tPA bolus or reperfusion. However, with tPA alone, at least one third of these nonresponders still achieved good outcomes at 3 months, suggesting the possibility of a “stunned brain” syndrome with delayed recovery. Several different mechanisms may potentially account for this phenomenon.

Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes

BackgroundInterruption of flow through of cerebral blood vessels results in acute ischemic stroke. Subsequent breakdown of the blood brain barrier increases cerebral injury by the development of vasogenic edema and secondary hemorrhage known as hemorrhagic transformation (HT). Diabetes is a risk factor for stroke as well as poor outcome of stroke. The current study tested the hypothesis that diabetes-induced changes in the cerebral vasculature increase the risk of HT and augment ischemic injury.MethodsDiabetic Goto-Kakizaki (GK) or control rats underwent 3 hours of middle cerebral artery occlusion and 21 h reperfusion followed by evaluation of infarct size, hemorrhage and neurological outcome.ResultsInfarct size was significantly smaller in GK rats (10 ± 2 vs 30 ± 4%, p < 0.001). There was significantly more frequent hematoma formation in the ischemic hemisphere in GK rats as opposed to controls. Cerebrovascular tortuosity index was increased in the GK model (1.13 ± 0.01 vs 1.34 ± 0.06, P < 0.001) indicative of changes in vessel architecture.ConclusionThese findings provide evidence that there is cerebrovascular remodeling in diabetes. While diabetes-induced remodeling appears to prevent infarct expansion, these changes in blood vessels increase the risk for HT possibly exacerbating neurovascular damage due to cerebral ischemia/reperfusion in diabetes.

A web-based telestroke system facilitates rapid treatment of acute ischemic stroke patients in rural emergency departments.

Patients in rural communities lack access to acute stroke therapies. Rapid administration of thrombolytic therapy increases the likelihood of a favorable outcome in ischemic stroke. We aimed to detail the safety, feasibility, and treatment times of thrombolytic therapy with a web-based telestroke system. At the Medical College of Georgia, we have developed a telestroke system (Remote Evaluation of Acute IsCHemic Stroke; REACH) in which emergency physicians in surrounding counties may consult stroke specialists at our institution. The web-based system allows the stroke consultant to obtain history, examine the patient with live video, and review computed tomography. A recommendation is made regarding the administration of tissue plasminogen activator (tPA) before patient transport to the tertiary medical center. A systematic review of the literature was conducted regarding the use of tPA in academic and community hospitals. Symptomatic hemorrhagic transformation and stroke onset-to-treatment times were compared between the REACH network and other stroke care delivery systems. Between February 2003 and March 2006, 50 patients were treated with intravenous tPA using the REACH telestroke system. There was one (2%) symptomatic hemorrhage. The mean onset-to-treatment time was 127.6 min (95% confidence interval 117.1-138.0) using REACH compared with 145.9 min (95% confidence interval 126.9-164.9) in our Emergency Department and 147.8 min in other published systems. REACH, a web-based telestroke system, facilitates the safe administration of thrombolytic therapy to patients within rural communities suffering an acute ischemic stroke.

Telestroke: extending stroke expertise into underserved areas

Telestroke systems offer the opportunity to extend stroke-care expertise into rural and underserved areas. These systems are being used to give alteplase to patients with stroke in previously underserved areas safely, effectively, and rapidly. Telestroke will probably play a large part in improving the quality of stroke care and in enrolling patients into clinical trials in rural and community hospitals. One such telestroke system, REACH (remote evaluation of acute ischaemic stroke), is a low-cost, web-based system that allows the consultant to access the system from work, home, or on the road. REACH is presently being used to give alteplase and guide acute stroke care in eight rural community hospitals in Georgia.

Treatment of acute intracerebral hemorrhage with ɛ-aminocaproic acid

AbstractIntroduction: Up to 40% of primary intracerebral hemorrhages (ICHs) expand within the first 24 hours (natural history). The authors aimed to study the safety and preliminary efficacy of ɛ-aminocaproic acid (EACA) in halting ICH enlargement. Methods: Consecutive patients with hematoma volumes ranging from 5 to 80 mL were recruited within 12 hours of ICH onset. A total of 5 g EACA was infused during 1 hour and then 1 g/hour for 23 hours. Hematoma volume was compared onbaseline, and 24–48-hour brain imaging. Consecutive untreated patients underwent the same imaging protocol. Results: Three of the first five patients treated had HE>33% of their baseline volume. HE occurred in two of the nine untreated patients. The 80% confidence interval for HE in the treated patients was 32–88%. No thrombotic or other serious adverse events were attributed to EACA. Conclusion: It is unlikely that the rate of HE in patients given EACA within 12 hours of ICH is less than the natural history rate, although this treatment appears to be safe.

The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial protocol: a randomized, blinded, efficacy trial of standard vs. intensive hyperglycemia management in acute stroke

Rationale Patients with acute ischemic stroke and hyperglycemia have worse outcomes than those without hyperglycemia. Intensive glucose control during acute stroke is feasible and can be accomplished safely but has not been fully assessed for efficacy. Aims The Stroke Hyperglycemia Insulin Network Effort trial aims to determine the safety and efficacy of standard vs. intensive glucose control with insulin in hyperglycemic acute ischemic stroke patients. Design This is a randomized, blinded, multicenter, phase III trial of approximately 1400 hyperglycemic patients who receive either standard sliding scale subcutaneous insulin (blood glucose range 80–179 mg/dL, 4·44–9·93 mmol/L) or continuous intravenous insulin (target blood glucose 80–130 mg/dL, 4·44–7·21 mmol/L) for up to 72 h, starting within 12 h of stroke symptom onset. The acute treatment phase is single blind (for the patients), but the final outcome assessment is double blind. The study is powered to detect a 7% absolute difference in favorable outcome at 90 days. Study outcomes The primary outcome is a baseline severity adjusted 90-day modified Rankin Scale score, defined as 0, 0–1, or 0–2, if the baseline National Institutes of Health Stroke Scale score is 3–7, 8–14, or 15–22, respectively. The primary safety outcome is the rate of severe hypoglycemia (<40 mg/dL, <2·22 mmol/L). Discussion This trial will provide important novel information about preferred management of acute ischemic stroke patients with hyperglycemia. It will determine the potential benefits and risks of intensive glucose control during acute stroke.