Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study. Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Recombinant activated factor VII for acute intracerebral hemorrhage: US phase IIA trial. The treatment of spontaneous intracerebral hemorrhage. A prospective randomized trial of surgical and conservative treatment. Heparin treatment in sinus venous thrombosis. Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1): a randomized, placebo-controlled safety study. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Randomised comparison between adrenaline injection alone and adrenaline injection plus heat probe treatment for actively bleeding ulcers.
The safety and the effectiveness of the surgical treatment of spontaneous intracerebral hemorrhage (ICH) remain controversial. To investigate the feasibility of urgent surgical evacuation of ICH, we conducted a small, randomized feasibility study of early surgical treatment versus current nonoperative management in patients with spontaneous supratentorial ICH.
                Patients with spontaneous supratentorial ICH who presented to 1 university and 2 community hospitals were randomized to surgical treatment or best medical treatment. Principal eligibility criteria were ICH volume >10 cm(3) on baseline CT scan with a focal neurological deficit, Glasgow Coma Scale score >4 at the time of enrollment, randomization and therapy within 24 hours of symptom onset, surgery within 3 hours of randomization, and no evidence for ruptured aneurysm or arteriovenous malformation. The primary end point was the 3-month Glasgow Outcome Scale (GOS). A good outcome was defined as a 3-month GOS score >3.
                Twenty patients were randomized over 24 months, 9 to surgical intervention and 11 to medical treatment. The median time from onset of symptoms to presentation at the treating hospitals was 3 hours and 17 minutes, the time from randomization to surgery was 1 hour and 20 minutes, and the time from onset of symptoms to surgery was 8 hours and 35 minutes. The likelihood of a good outcome (primary outcome measure: GOS score >3) for the surgical treatment group (56%) did not differ significantly from the medical treatment group (36%). There was no significant difference in mortality at 3 months. Analysis of the secondary 3-month outcome measures showed a nonsignificant trend toward a better outcome in the surgical treatment group versus the medical treatment group for the median GOS, Barthel Index, and Rankin Scale and a significant difference in the National Institutes of Health Stroke Scale score (4 versus 14; P=0.04).
                Very early surgical treatment for acute ICH is difficult to achieve but feasible at academic medical centers and community hospitals. The trend toward less 3-month morbidity with surgical intervention in patients with spontaneous supratentorial ICH warrants further investigation of very early clot removal in larger randomized clinical trials. Hematoma growth occurs in 38% of intracerebral hemorrhage (ICH) patients scanned by computed tomography (CT) within 3 hours of onset. Activated recombinant factor VII (rFVIIa) promotes hemostasis at sites of vascular injury and may minimize hematoma growth after ICH.
                In this randomized, double-blind, placebo-controlled, dose-escalation trial, 48 subjects with ICH diagnosed within 3 hours of onset were treated with placebo (n=12) or rFVIIa (10, 20, 40, 80, 120, or 160 microg/kg; n=6 per group). The primary endpoint was the frequency of adverse events (AEs). Safety assessments included serial electrocardiography (ECG), troponin I and coagulation testing, lower extremity Doppler ultrasonography, and calculation of edema:ICH volume ratios.
                Mean age was 61 years (range, 30 to 93) and 57% were male. At admission, mean National Institutes of Health Stroke Scale (NIHSS) score was 14 (range, 1 to 26), median Glasgow Coma Scale score was 14 (range, 6 to 15), and mean ICH volume was 21 mL (range, 1 to 151). Mean time from onset to treatment was 181 minutes (range, 120 to 265). Twelve serious AEs occurred, including 5 deaths (mortality 11%). Six AEs were considered possibly treatment-related, including rash, vomiting, fever, ECG T-wave inversion, and 2 cases of deep vein thrombosis (placebo and 20-microg/kg groups). No myocardial ischemia, consumption coagulopathy, or dose-related increase in edema:ICH volume occurred.
                This small phase II trial evaluated a wide range of rFVIIa doses in acute ICH and raised no major safety concerns. Larger studies are justified to determine whether rFVIIa can safely and effectively limit ICH growth. Ultra-early hemostatic therapy may improve outcome after intracerebral hemorrhage (ICH) by preventing rebleeding and hematoma expansion. We conducted this trial to evaluate the safety of activated recombinant factor VII (rFVIIa; NovoSeven) for preventing early hematoma growth in acute ICH.
                In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial, 40 patients diagnosed with ICH by computed tomography within 3 hours of onset were treated with placebo or 5, 20, 40, or 80 microg/kg of rFVIIa ( n = 8 per group). Patients with any history of thromboembolic or vaso-occlusive disease were excluded. The primary endpoint was the frequency of adverse events (AEs).
                Mean age was 65 years (range 34 - 91) and the median admission Glasgow Coma Scale score was 14.5 (range 6 to 15). Mean ICH volume was 17 +/- 19 mL; nearly three-quarters were located in the basal ganglia ( n = 29). The mean interval from onset to treatment was 178 +/- 41 minutes. Thirty-three patients experienced 186 AEs, which occurred with similar frequency in the five groups. There were 10 thromboembolic AEs, including one case of deep vein thrombosis (20 microg g/kg group); one case of cerebral infarction (placebo); two cases of pulmonary embolism (20 and 40 microg g/kg groups); and six instances of ischemic ECG changes or cardiac enzyme elevation (placebo [ n = 2], 20 microg g/kg [ n = 1], 40 microg g/kg [ n = 1], and 80 microg g/kg [ n = 2] groups). No consumption coagulopathy or dose-related increase in edema-to-ICH volume ratio occurred.
                Ultra-early rFVIIa treatment for ICH was associated with a reasonable safety profile in this preliminary study across a wide range of dosages. Further research is warranted to investigate the safety and potential efficacy of rFVIIa for minimizing ICH growth. In a prospective study, 52 patients with a spontaneous supratentorial intracerebral hematoma (ICH) were randomly assigned to receive emergency surgery or conservative treatment within 48 hours after the bleed. Patients with a decreased level of consciousness and/or a severe neurological deficit were admitted to the study. The overall mortality rate at 6 months was 42%: 10 (38%) of the 26 patients in the conservative group and 12 (46%) of the 26 in the surgical group. Six (20%) of the 30 survivors at 6 months were able to conduct their activities of daily living independently: five (31%) of the 16 patients in the conservative group and one (7%) of the 14 in the operative group. These differences are not statistically significant. The mortality rate of semicomatose or stuporous patients (Glasgow Coma Scale score 7 to 10) was statistically significantly lower in the surgical group (none of the four patients) than in the conservative group (four of five patients) (p less than 0.05); however, all surviving patients in this subgroup were severely disabled. The study suggests that surgical treatment of this category of patients with ICH does not offer any definite advantage over conservative treatment. In semicomatose or stuporous patients, surgery may improve the length of survival, but the quality of life remains poor. Treatment of sinus venous thrombosis (SVT) is controversial. Although heparin has been used for this condition, many investigators have opposed its use because of the frequent occurrence of intracranial haemorrhage (ICH) and SVT. Therefore we have evaluated anticoagulation with adjusted-dose intravenous heparin for treatment of aseptic SVT in a randomised, blinded (patient and observer), placebo-controlled study in 20 patients (10 heparin, 10 placebo). The clinical course of the two groups, as judged by a newly designed SVT-severity scale, started to differ in favour of the heparin group after 3 days of treatment (p less than 0.05, Mann-Whitney U-test) and the difference remained significant (p less than 0.01) after 8 days of treatment. After 3 months, 8 of the heparin-treated patients had a complete clinical recovery and 2 had slight residual neurological deficits. In the placebo group, only 1 patient had a complete recovery, 6 patients had neurological deficits, and 3 patients died (p less than 0.01, modified Fisher's exact test). An additional retrospective study on the relation between heparin treatment and ICH in SVT patients was based on 102 patients, 43 of whom had an ICH. 27 of these patients were treated with dose-adjusted, intravenous heparin after the ICH. Of these 27 patients, 4 died (mortality 15%), and 14 patients completely recovered. Of the 13 patients that did not receive heparin after ICH, 9 died (mortality 69%) and only 3 patients completely recovered. We conclude that anticoagulation with dose-adjusted intravenous heparin is an effective treatment in patients with SVT and that ICH is not a contraindication to heparin treatment in these patients. To perform a single-center pilot investigation of early hematoma removal in patients with intracerebral hemorrhage (ICH).
                Considerable debate remains regarding the utility of surgical clot evacuation for ICH.
                This was a prospective trial of open craniotomy within 12 hours of ICH symptom onset versus best medical therapy. Patients were eligible if they had a nontraumatic ICH >9 mL with significant neurologic impairment and were prepared for surgery within 12 hours of symptom onset. The study included a prospective registry of patients and a randomized trial.
                The registry group included 34 medical and seven surgical patients. The surgical group had larger hemorrhages (median, 96 mL) and a lower Glasgow Coma Scale (GCS) score (median, 10) compared with the medical group (33 mL; GCS score, 13). Six-month mortality was less in the medical group (36%) compared with the surgical group (54%). In the randomized series, median ICH volumes were similar in the surgical group (n = 17; 49 mL) compared with the medical group (n = 17; 44 mL). Median GCS score was also similar (medical, 10; surgical, 11). Mortality was lower in the surgical group (6%) compared with the medical group (24%) at 1 month, but similar at 6 months (surgical group, 17%; medical group, 24%).
                A trial of early surgery for ICH is feasible. This study represents the largest prospective, randomized series of surgery for ICH. A modest early mortality benefit for surgery is possible, but long-term benefit for surgery was not established in this single-center pilot investigation. Direct thrombin inhibitors, including argatroban, represent an anticoagulant class distinct from heparins. We investigated the safety of 2 levels of argatroban anticoagulation in acute ischemic stroke.
                This multicenter, randomized, double-blinded, placebo-controlled study included 171 patients with acute (< or =12 hours from onset) stroke and National Institutes of Health Stroke Scale (NIHSS) scores of 5 to 22. Patients received continuous intravenous argatroban (100 microg/kg bolus) at 3 microg/kg per minute (n=59) or 1 microg/kg per minute (n=58), respectively, adjusted to target activated partial thromboplastin times (aPTTs) 2.25x and 1.75x baseline or placebo (n=54) for 5 days. The primary outcome was symptomatic intracranial hemorrhage (ICH) at 30 days.
                Baseline characteristics including neurologic deficits (median NIHSS score 9) were comparable between groups. Argatroban at mean doses of 2.7 and 1.2 microg/kg per minute increased aPTTs significantly (P<0.001), with mean aPTTs at or near target values throughout infusion. Symptomatic ICH was not significantly different between groups (high-dose argatroban, 5.1%; low-dose argatroban, 3.4%; placebo, 0%; P> or =0.18), with 3 events during argatroban infusion and 2 events > or =7 days after stopping infusion. No significant between-group differences occurred in asymptomatic ICH (7 events), major systemic hemorrhage (no event), or 90-day mortality (13.4% overall).
                In this first North American randomized, double-blinded, placebo-controlled study of direct thrombin inhibition in acute ischemic stroke, argatroban at each dose evaluated significantly prolonged aPTTs without increasing ICH or major bleeding. These results suggest that argatroban provides safe anticoagulation in acute ischemic stroke, warranting future studies powered to evaluate its efficacy and more precisely estimate event rates. The purpose of this study was to test the feasibility, efficacy, and safety of combined intravenous (IV) and local intra-arterial (IA) recombinant tissue plasminogen activator (r-TPA) therapy for stroke within 3 hours of onset of symptoms.
                This was a double-blind, randomized, placebo-controlled multi-center Phase I study of IV r-TPA or IV placebo followed by immediate cerebral arteriography and local IA administration of r-TPA by means of a microcatheter. Treatment activity was assessed by improvement on the National Institutes of Health Stroke Scale Score (NIHSSS) at 7 to 10 days. The Barthel Index, modified Rankin Scale, and the Glasgow Outcome Scale measured 3-month functional outcome. Arterial recanalization rates and their relation to total r-TPA dose and time to lysis were measured. Rates of life-threatening bleeding, intracerebral hemorrhage (ICH), or other bleeding complications assessed safety.
                Thirty-five patients were randomly assigned, 17 into the IV/IA group and 18 into the placebo/IA group. There was no difference in the 7- to 10-day or the 3-month outcomes, although there were more deaths in the IV/IA group. Clot was found in 22 of 34 patients. Recanalization was better (P=0. 03) in the IV/IA group with TIMI 3 flow in 6 of 11 IV/IA patients versus 1 of 10 placebo/IA patients and correlated to the total dose of r-TPA (P=0.05). There was no difference in the median treatment intervals from time of onset to IV treatment (2.6 vs 2.7 hours), arteriography (3.3 vs 3.0 hours), or clot lysis (6.3 vs 5.7 hours) between the IV/IA and placebo/IA groups, respectively. A direct relation between NIHSSS and the likelihood of the presence of a clot was identified. Eight ICHs occurred; all were hemorrhagic infarctions. There were no parenchymal hematomas. Symptomatic ICH within 24 hours occurred in 1 placebo/IA patient only. Beyond 24 hours, symptomatic ICH occurred in 2 IV/IA patients only. Life-threatening bleeding complications occurred in 2 patients, both in the IV/IA group. Moderate to severe bleeding complications occurred in 2 IV/IA patients and 1 placebo/IA patient.
                This pilot study demonstrates combined IV/IA treatment is feasible and provides better recanalization, although it was not associated with improved clinical outcomes. The presence of thrombus on initial arteriography was directly related to the baseline NIHSSS. This approach is technically feasible. The numbers of symptomatic ICH were similar between the 2 groups, which suggests that this approach may be safe. Further study is needed to determine the safety and effectiveness of this new method of treatment. Such studies should address not only efficacy and safety but also the cost-benefit ratio and quality of life, given the major investment in time, personnel, and equipment required by combined IV and IA techniques. To compare endoscopic adrenaline injection alone and adrenaline injection plus heat probe for the treatment of actively bleeding peptic ulcers.
                Randomised prospective study of patients admitted with actively bleeding peptic ulcers.
                One university hospital.
                276 patients with actively bleeding ulcers detected by endoscopy within 24 hours of admission: 136 patients were randomised to endoscopic adrenaline injection alone and 140 to adrenaline injection plus heat probe treatment.
                Initial endoscopic haemostasis; clinical rebleeding; requirement for operation; requirement for blood transfusion; hospital stay, ulcer healing at four weeks; and mortality in hospital.
                Initial haemostasis was achieved in 131/134 patients (98%) who received adrenaline injection alone and 135/136 patients (99%) who received additional heat probe treatment (P = 0.33). Outcome as measured by clinical rebleeding (12 v 5), requirement for emergency operation (14 v 8), blood transfusion (2 v 3 units), hospital stay (4 v 4 days), ulcer healing at four weeks (79.1% v 74%), and in hospital mortality (7 v 8) were not significantly different in the two groups. In the subgroup of patients with spurting haemorrhage 8/27 (29.6%; 14.5% to 50.3%) patients from the adrenaline injection alone group and 2/31 (6.5%; 1.1% to 22.9%) patients from the dual treatment group required operative intervention. The relative risk of this was lower in the dual treatment group (0.17; 0.03 to 0.87). Hospital stay was significantly shorter in the dual treatment group than the adrenaline injection alone group (4 v 6 days, P = 0.01).
                The addition of heat probe treatment after endoscopic adrenaline injection confers an advantage in ulcers with spurting haemorrhage.
Haemostatic drugs cannot be recommended for the treatment of acute spontaneous ICH in clinical practice, but a large RCT would be justified.