Derk Krieger

Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke Feasibility, Safety, and Efficacy in the First Year of Clinical Practice

BACKGROUND AND PURPOSE The feasibility, safety, and efficacy of intravenous tissue plasminogen activator (t-PA) for patients with acute ischemic stroke in clinical practice need to be assessed. METHODS We initiated a prospective open-label study at a university hospital and two community hospitals in Houston, Tex, immediately after the publication of the National Institute of Neurological Disorders and Stroke (NINDS) t-PA study. A total of 30 patients, age 32 to 90 years, were treated with 0.9 mg/kg of intravenous t-PA (maximum dose, 90 mg) within 3 hours of acute ischemic stroke between December 1995 and December 1996. RESULTS Six percent (6%) of all patients hospitalized with ischemic stroke received intravenous t-PA at the university hospital and 1.1% at the community hospitals. The rates of total, symptomatic, and fatal intracerebral hemorrhage were 10%, 7%, and 3%. Thirty-seven percent (37%) of patients recovered to fully independent function. The average time from stroke onset to emergency department arrival was 57 minutes; emergency department arrival to computed tomography scan 41 minutes; and computed tomography scan to administration of treatment 59 minutes. CONCLUSIONS When treatment guidelines are carefully followed in an urban hospital setting, intravenous t-PA for acute ischemic stroke is feasible and shows safety and efficacy comparable to the results of the NINDS study.

Cooling for Acute Ischemic Brain Damage (COOL AID) An Open Pilot Study of Induced Hypothermia in Acute Ischemic Stroke

Background and Purpose— Hypothermia is effective in improving outcome in experimental models of brain infarction. We studied the feasibility and safety of hypothermia in patients with acute ischemic stroke treated with thrombolysis. Methods— An open study design was used. All patients presented with major ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score >15) within 6 hours of onset. After informed consent, patients with a persistent NIHSS score of >8 were treated with hypothermia to 32±1°C for 12 to 72 hours depending on vessel patency. All patients were monitored in the neurocritical care unit for complications. A modified Rankin Scale was measured at 90 days and compared with concurrent controls. Results— Ten patients with a mean age of 71.1±14.3 years and an NIHSS score of 19.8±3.3 were treated with hypothermia. Nine patients served as concurrent controls. The mean time from symptom onset to thrombolysis was 3.1±1.4 hours and from symptom onset to initiation of hypothermia was 6.2±1.3 hours. The mean duration of hypothermia was 47.4±20.4 hours. Target temperature was achieved in 3.5±1.5 hours. Noncritical complications in hypothermia patients included bradycardia (n=5), ventricular ectopy (n=3), hypotension (n=3), melena (n=2), fever after rewarming (n=3), and infections (n=4). Four patients with chronic atrial fibrillation developed rapid ventricular rate, which was noncritical in 2 and critical in 2 patients. Three patients had myocardial infarctions without sequelae. There were 3 deaths in patients undergoing hypothermia. The mean modified Rankin Scale score at 3 months in hypothermia patients was 3.1±2.3. Conclusion— Induced hypothermia appears feasible and safe in patients with acute ischemic stroke even after thrombolysis. Refinements of the cooling process, optimal target temperature, duration of therapy, and, most important, clinical efficacy, require further study.

Serum Glucose Level and Diabetes Predict Tissue Plasminogen Activator–Related Intracerebral Hemorrhage in Acute Ischemic Stroke

BACKGROUND AND PURPOSE Five pretreatment variables (P<0.1 univariate analysis), including serum glucose (>300 mg/dL), predicted symptomatic intracerebral hemorrhage (ICH) in the National Institute of Neurological Disorders and Stroke rtPA trial. We retrospectively studied stroke patients treated <3 hours from onset with intravenous rtPA at 2 institutions to evaluate the role of these variables in predicting ICH. METHODS Baseline characteristics, including 5 prespecified variables (age, baseline glucose, smoking status, National Institutes of Health Stroke Scale [NIHSS] score, and CT changes [>33% middle cerebral artery territory hypodensity]), were reviewed in 138 consecutive patients. Variables were evaluated by logistic regression as predictors of all hemorrhage (including hemorrhagic transformation) and symptomatic hemorrhage on follow-up CT scan. Variables significant at P<0.25 level were included in a multivariate analysis. Diabetes was substituted for glucose in a repeat analysis. RESULTS Symptomatic hemorrhage rate was 9% (13 of 138). Any hemorrhage rate was 30% (42 of 138). Baseline serum glucose (5.5-mmol/L increments) was the only independent predictor of both symptomatic hemorrhage [OR, 2.26 (CI, 1.05 to 4.83), P=0.03] and all hemorrhage [OR, 2.26 (CI, 1.07 to 4.69), P=0.04]. Serum glucose >11.1 mmol/L was associated with a 25% symptomatic hemorrhage rate. Baseline NIHSS (5-point increments) was an independent predictor of all hemorrhage only [OR, 12.42 (CI, 1.64 to 94.3), P=0.01]. Univariate analysis demonstrated a trend for nonsmoking as a predictor of all hemorrhage [OR, 0.45 (CI, 0.19 to 1. 08), P=0.07]. Diabetes was also an independent predictor of ICH when substituted for glucose in repeat analysis. CONCLUSIONS Serum glucose and diabetes were predictors of ICH in rtPA-treated patients. This novel association requires confirmation in a larger cohort.

Cooling for Acute Ischemic Brain Damage (COOL AID) A feasibility trial of endovascular cooling

Objective: To report results of a randomized pilot clinical feasibility trial of endovascular cooling in patients with ischemic stroke. Methods: Forty patients with ischemic stroke presenting within 12 hours of symptom onset were enrolled in the study. An endovascular cooling device was inserted into the inferior vena cava of those randomized to hypothermia. A core body temperature of 33 °C was targeted for 24 hours. All patients underwent clinical assessment and MRI initially, at days 3 to 5 and days 30 to 37. Results: Eighteen patients were randomized to hypothermia and 22 to receive standard medical management. Thirteen patients reached target temperature in a mean of 77 ± 44 minutes. Most tolerated hypothermia well. Clinical outcomes were similar in both groups. Mean diffusion-weighted imaging (DWI) lesion growth in the hypothermia group (n = 12) was 90.0 ± 83.5% compared with 108.4 ± 142.4% in the control group (n = 11) (NS). Mean DWI lesion growth in patients who cooled well (n = 8) was 72.9 ± 95.2% (NS). Conclusions: Induced moderate hypothermia is feasible using an endovascular cooling device in most patients with acute ischemic stroke. Further studies are needed to determine if hypothermia improves outcome.

Correlation between ammonia levels and the severity of hepatic encephalopathy

PURPOSE Because the correlation between ammonia levels and the severity of hepatic encephalopathy remains controversial, we prospectively evaluated the correlation in 121 consecutive patients with cirrhosis. METHODS The diagnosis of hepatic encephalopathy was based on clinical criteria, and the severity of hepatic encephalopathy was based on the West Haven Criteria for grading of mental status. Arterial and venous blood samples were obtained from each patient. Four types of ammonia measurements were analyzed: arterial and venous total ammonia, and arterial and venous partial pressure of ammonia. Spearman rank correlations (r(s)) were calculated. RESULTS Of the 121 patients, 30 (25%) had grade 0 encephalopathy (no signs or symptoms), 27 (22%) had grade 1, 23 (19%) had grade 2, 28 (23%) had grade 3, and 13 (11%) had grade 4 (the most severe signs and symptoms). Each of the four measures of ammonia increased with the severity of hepatic encephalopathy: arterial total ammonia (r(s) = 0.61, P < or = 0.001), venous total ammonia (r(s) = 0.56, P < or = 0.001), arterial partial pressure of ammonia (r(s) = 0.55, P < or = 0.001), and venous partial pressure of ammonia (r(s) = 0.52, P < or = 0.001). CONCLUSION Ammonia levels correlate with the severity of hepatic encephalopathy. Venous sampling is adequate for ammonia measurement. There appears to be no additional advantage of measuring the partial pressure of ammonia compared with total ammonia levels.

Early Clinical and Radiological Predictors of Fatal Brain Swelling in Ischemic Stroke

BACKGROUND AND PURPOSE Early identification of acute stroke patients at risk of fatal brain swelling is necessary to facilitate implementation of aggressive therapies. Initial clinical, laboratory, and CT characteristics that may be used as selection criteria were analyzed to determine predictors of herniation and neurological death. METHODS Data from the placebo arm of the Lubeluzole-International-9 trial were reviewed to identify patients with fatal brain edema. Early clinical, laboratory, and radiographic parameters were evaluated in a case-control design. Initial CT scans were analyzed for early ischemic abnormalities by 2 blinded investigators. RESULTS Twenty-three patients died from brain swelling, with minimum baseline National Institutes of Health Stroke Scale (NIHSS) scores of 20 (n=12; mean, 23.2+/-1.8) with left and 15 (n=11; mean, 17.6+/-2.2) with right hemispheric infarctions (P=0. 0001). A sample of 112 subjects with comparably severe strokes, but who did not die from brain swelling, was selected from the remaining population according to the same NIHSS scores. Among clinical and laboratory characteristics, nausea/vomiting within 24 hours after onset (odds ratio [OR], 5.1; 95% CI, 1.7 to 15.3; P=0.003) and 12-hour systolic blood pressure >/=180 mm Hg (OR, 4.2; 95% CI, 1.4 to 12.9; P=0.01) were independently associated with fatal brain swelling. Among radiographic factors, only hypodensity of >50% of the middle cerebral artery territory on initial CT scan was an independent predictor (OR, 6.1; 95% CI, 2.3 to 16.6; P=0.0004). CONCLUSIONS Patients with baseline NIHSS score >/=20 with left or >/=15 with right hemispheric infarctions within 6 hours of symptom onset who also have nausea/vomiting or >50% middle cerebral artery territory hypodensity are at high risk for developing fatal brain swelling.

European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage

Background Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome. In view of recent randomized controlled trials (RCTs) of the management of ICH, the European Stroke Organisation (ESO) has updated its evidence-based guidelines for the management of ICH. Method A multidisciplinary writing committee of 24 researchers from 11 European countries identified 20 questions relating to ICH management and created recommendations based on the evidence in RCTs using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results We found moderate- to high-quality evidence to support strong recommendations for managing patients with acute ICH on an acute stroke unit, avoiding hemostatic therapy for acute ICH not associated with antithrombotic drug use, avoiding graduated compression stockings, using intermittent pneumatic compression in immobile patients, and using blood pressure lowering for secondary prevention. We found moderate-quality evidence to support weak recommendations for intensive lowering of systolic blood pressure to <140 mmHg within six-hours of ICH onset, early surgery for patients with a Glasgow Coma Scale score 9–12, and avoidance of corticosteroids. Conclusion These guidelines inform the management of ICH based on evidence for the effects of treatments in RCTs. Outcome after ICH remains poor, prioritizing further RCTs of interventions to improve outcome.

Therapeutic Hypothermia for Acute Ischemic Stroke: What Do Laboratory Studies Teach Us?

Background and Purpose— The significance of brain temperature to outcome in cerebral ischemia is recognized. Numerous variations of depth, duration, and delay of cooling have been studied in animal models. It is important to become familiar with these studies to design appropriate clinical trials. With that in mind, a critical review of the pertinent literature is presented, taking into consideration potential limitations in translating such laboratory work to the clinical level. Methods— Hypothermia is an especially robust neuroprotectant in the laboratory and has been shown to alter many of the damaging effects of cerebral ischemia. Most laboratory research on therapeutic cooling in cerebral ischemia has been conducted in rodent models of temporary and permanent middle cerebral artery occlusion and report the effects of mild or moderate hypothermia arranged during or after ischemia. Results— Intraischemic cooling vastly reduces infarct size in most occlusion models. Tissue salvage with delayed onset of cooling is less dramatic but is commonly observed when cooling is begun within 60 minutes of stroke onset in permanent and 180 minutes of stroke onset in temporary occlusion models. Prolonged postischemic cooling further enhances efficacy. Conclusions— Laboratory studies have shown that intraischemic hypothermia is more protective than postischemic hypothermia and more benefit is conferred with temporary occlusion than permanent occlusion models. The efficacy of postischemic hypothermia is critically dependent on the duration and depth of hypothermia and its timing relative to ischemia.

Acetaminophen for altering body temperature in acute stroke: a randomized clinical trial.

Background and Purpose— Mild alterations in temperature have prominent effects on ischemic cell injury and stroke outcome. Elevated core body temperature (CBT), even if mild, may exacerbate neuronal injury and worsen outcome, whereas hypothermia is potentially neuroprotective. The antipyretic effects of acetaminophen were hypothesized to reduce CBT. Methods— This was a randomized, controlled clinical trial at 2 university hospitals. Patients were included if they had stroke within 24 hours of onset of symptoms, National Institutes of Health Stroke Scale (NIHSS) score ≥5, initial CBT <38.5°C, and white blood cell count <12 600 cells/mm3; they were excluded if they had signs of infection, severe medical illness, or contraindication to acetaminophen. CBT was measured every 30 minutes. Patients were randomized to receive acetaminophen 650 mg or placebo every 4 hours for 24 hours. The primary outcome measure was mean CBT during the 24-hour study period; the secondary outcome measure was the change in NIHSS. Results— Thirty-nine patients were randomized. Baseline CBT was the same: 36.96°C for acetaminophen versus 36.95°C for placebo (P =0.96). During the study period, CBT tended to be lower in the acetaminophen group (37.13°C versus 37.35°C), a difference of 0.22°C (95% CI, −0.08°C to 0.51°C;P =0.14). Patients given acetaminophen tended to be more often hypothermic <36.5°C (OR, 3.4; 95% CI, 0.83 to 14.2;P =0.09) and less often hyperthermic >37.5°C (OR, 0.52; 95% CI, 0.19 to 1.44;P =0.22). The change in NIHSS scores from baseline to 48 hours did not differ between the groups (P =0.93). Conclusions— Early administration of acetaminophen (3900 mg/d) to afebrile patients with acute stroke may result in a small reduction in CBT. Acetaminophen may also modestly promote hypothermia <36.5°C or prevent hyperthermia >37.5°C. These effects are unlikely to have robust clinical impact, and alternative or additional methods are needed to achieve effective thermoregulation in stroke patients.

Serum neuron-specific enolase as early predictor of outcome after cardiac arrest

OBJECTIVE To examine the prognostic value of serum neuron-specific enolase for early prediction of outcome in patients at risk for anoxic encephalopathy after cardiac arrest. DESIGN Prospective study. SETTING Coronary intensive care unit of the University of Heidelberg. PATIENTS Forty-three patients (66.8 +/- 12.7 [SD] yrs, range 33 to 85) who had had either primary or secondary cardiac arrest, followed by cardiopulmonary resuscitation (CPR). INTERVENTIONS Serial blood samples and clinical examinations. MEASUREMENTS AND MAIN RESULTS Serum neuron-specific enolase concentrations were determined after CPR on 7 consecutive days. Twenty-five patients remained comatose and subsequently died; 18 patients survived the first 3 months and had no relevant functional deficit at 3-month follow-up. Neuron-specific enolase concentrations were correlated with neurologic outcome. Concentrations of >33 ng/mL predicted persistent coma with a high specificity (100%) and a positive predictive value of 100%. Overall sensitivity was 80%, with a negative predictive value of 78%. Serum concentrations of neuron-specific enolase exceeded this cutoff value no more than 3 days after cardiac arrest in 95% of patients in whom these concentrations had exceeded 33 ng/mL. CONCLUSIONS In patients who have been resuscitated after cardiac arrest, serum neuron-specific enolase concentrations of >33 ng/mL predict persistent coma with a high specificity. Values below this cutoff level do not necessarily indicate complete recovery, because this method has a sensitivity of 80%.