[How can we optimize medical orderings in intensive care unit (ICU)?]. / Optimisation des prescriptions en réanimation.

OBJECTIVES: To evaluate whether intensivists would accept to optimize their orderings of biological samplings, x-rays and target drugs and to assess the consequence on patient's outcome. STUDY DESIGN: Monocentric evaluation of medical economic procedure. METHODS: Meetings of consultants, registrars and residents started on Dec 21, 2006 with two to three sessions a year in order to evaluate the process of medical ordering. The physicians and pharmacists gave the results of orderings at each meeting. Orderings of systematic samplings, bedside x-rays and unjustified expansive drugs were discouraged, but target samplings and lung ultrasonography were encouraged. New residents were systematically taught about this programme. Meanwhile, monthly morbidity-mortality meetings were pursued in order to assess the consequences of this politics. RESULTS: While ICU total production increased by 3.4% and potentially evitable deaths decreased by 34%, annual expenses decreased by approximatively € 777,000 from 2006 to 2008. This was due to decreased orderings in biology by 30%, bedside x-rays by 10%, computed tomographic scans by 16% and target drugs by 35%. However, an increased ordering in four target drugs was observed in 2008 as compared with 2007. CONCLUSION: Multidisciplinary optimization of medical ordering can be efficient in ICU. However, a profit-sharing with ordering physicians would be necessary to prolong these effects.

Danaparoid cross-reactivity with heparin-induced thrombocytopenia antibodies: report of 12 cases.

PURPOSE: Danaparoid is a safe and effective drug for the treatment of heparin-induced thrombocytopenia (HIT). We describe an uncommon complication: danaparoid cross-reactivity with HIT antibodies. DESIGN AND SETTING: A retrospective observational multicenter study on HIT was conducted in France. In this study concerning HIT patients treated with lepirudin, 12 patients were treated with lepirudin because danaparoid cross-reacted with the heparin-dependent antibodies. RESULTS: Three groups of situations can be separated. In a first group, four patients received a short course of danaparoid until their initial functional HIT assay showed a cross-reactivity between danaparoid and HIT antibodies. One patient presented a fatal thrombotic complication but the relationship between this thrombotic complication and danaparoid cross-reactivity cannot be certain. In a second group, four patients received for 4 days at least a danaparoid treatment while the initial functional test did not show any danaparoid cross-reactivity. During danaparoid treatment, no significant increase of platelet count was observed and two patients presented a fatal thrombotic complication. In a third group, cross-reactivity between danaparoid and HIT antibodies was not checked before danaparoid therapy. During danaparoid treatment, no significant increase of platelet count was observed and the four patients developed a venous thromboembolic complication. CONCLUSION: Absence of any increase in platelet count after 3 to 5 days of danaparoid therapy and/or the occurrence of a new thrombotic event should lead to danaparoid cross-reactivity suspicion. However, before attributing thrombotic complications to danaparoid cross-reactivity, it is crucial to verify that the patients received the recommended danaparoid dosage regimen.

[Management of a high risk of thrombosis patient with drug-eluting stents undergoing a complete gastrectomy]. / Stratégie de prise en charge d'un patient porteur d'endoprothèses coronaires pharmacoactives à haut risque thrombotique pour une gastrectomie totale.

We report the case of a 70-year-old patient, with two drug-eluting stents (DES), scheduled for a complete gastrectomy for a gastric cancer. This case underlines management problems regarding a patient with a high risk of DES thrombosis in case of AAP withdrawal and a high risk of bleeding in case of AAP maintenance. At this time, no evidence-based recommendation is available for clinicians to manage these patients. Our strategy was therefore based on platelet function monitoring test, which is however neither available in clinical practice nor validated to predict haemorrhagic risk. Several biologic tests are under study; they could be useful to guide perioperative management of antiplatelet therapy in the clinical setting of surgical patients with DES.

Treatment of inherited protein C deficiency by replacement therapy with the French purified plasma-derived protein C concentrate (PROTEXEL).

BACKGROUND/OBJECTIVES: A multicentre retrospective study was performed to assess the efficacy/safety of a French purified plasma-derived protein C (PC) concentrate in inherited PC deficiency. MATERIALS AND METHODS: Nine patients were enrolled, five children aged < 5 weeks, among whom four with a severe deficiency were homozygous, and four patients < 37 years with PC levels ranging 14-25%, including one compound heterozygous. RESULTS: Thirty replacement therapy courses were recorded with mean PC dosages ranging between 24-90 IU/kg/day for prophylactic courses and 51-209 IU/kg/day for treatment courses. Recoveries varied between 0.8 and 1.12% IU/kg in preventive situations and between 1.09 and 1.91% IU/kg for treatment courses; 23 treatment courses were performed in patients aged 1 day to 18 years, 19 out of 23 treatments resulted in complete recovery with no sequelae. Treatment efficacy was difficult to assess in four out of 23 cases because the thrombotic event was not confirmed in one case and due to late treatment initiation in the three other cases. Seven prophylactic treatments were used either in association of vitamin K antagonists or to prevent thrombotic events due to vitamin K antagonist introduction or withdrawal. The safety assessed during 914 infusions was excellent. No abnormal bleeding was reported, including with high doses, during surgery, with heparin therapy. CONCLUSIONS: Replacement therapy with this French PC concentrate is safe and effective in patients with inherited PC deficiency.

[Coronary stents and anaesthesia]. / Endoprothèses coronaires et anesthésie.

The coronary stents are widely used to prevent coronary restenosis after percutaneous coronary intervention. Dual antiplatelet therapy (acetyl salicylic acid and a thienopyridine-clopidogrel or ticlopidine) are prescribed at least during six weeks after conventional stent and six months after drug eluting stent insertion to prevent stent thrombosis. When an invasive procedure is required, a risk of stent thrombosis arises after stopping antiplatelet therapy and a risk of bleeding when continuing this treatment. Therefore, cardiologists should choose carefully the type of coronary stent before insertion and concerned physicians (anaesthesiologists, surgeons, cardiologists) should decide a perioperative strategy in these high-risk patients.

[Predictive value of D-dimer assay in superficial thrombophlebitis of the lower limbs]. / Valeur des D-dimères lors des thromboses veineuses superficielles des membres inférieurs.

OBJECTIVE: The negative predictive value of D-dimer (DD) assay in patients with venous thromboembolic disease is well established for deep vein thrombosis and pulmonary embolism. Little is known about the value of DD assay in patients with superficial thrombophlebitis (ST). The purpose of this study was to assess the value of DD assay in patients with ST of the lower limb. METHOD: The study group was composed of 100 consecutive patients, irrespective of age. Patients with clinical manifestations suggestive of ST of the lower limbs with positive duplex color Doppler evidence confirming the diagnosis and DD assay results (Vidas D-Dimer Exclusion) within 24 hours were included in the study. Patients with thrombosis in another site in addition to the superficial vein of the lower limb, those taking anticoagulants for more than 48 hours, and those with a condition known to potentially elevate DD levels were excluded. The volume of the thrombus was determined echographically and reported as mean diameter and length. RESULTS: Sixty-two women and 38 men were included. Mean age (+/- 5) was 58 years +/- 13.48 (range 18-90; median: 57). The ST involved the Great saphenous (n=74), the small saphenous (n=11) or another vein (n=15). Mean thrombus volume was 4453 mm(3) +/- 7101 (range 94-38484; median: 1751). Mean DD level was 829 ng/ml +/- 516.72 (range 100-2567; median: 715.5). DD assay was negative (<500 ng/ml) in 32 patients (32%) and positive in 68 (68%). For these three items, there was no significant difference between ST with and without varicose veins. DD assay was always positive (>or=500 ng/ml) in all patients aged over 70 years (n=22). In patients aged less than 70 years (n=78), DD assay was positive in 46 (59%) and negative in 32 (41%). DD level was positively correlated with thrombus volume in patients aged less than 70 years (P<0.0001). ROC analysis, sensitivity as a function of specificity by thrombus volume for the entire population, determined the usefulness of a negative DD assay. Considering the critical threshold at 5914 mm(3), sensitivity was 1.0 (95CI 0.89-1.0), with 0.29 specificity (95CI 0.19-0.42), 1.00 negative predictive value and 0.75 positive predictive value. However, the thrombus volume was less than this threshold value in three of the nine cases of ST with extension to the terminal portion of the saphenous. CONCLUSION: A positive DD assay was observed in 68% of patients with ST, with no significant difference with or without varicose veins. The test was positive in all patients aged over 70 years and in 59% of those aged under 70 years. There was a correlation between DD level and thrombus volume, yielding a threshold volume (5914 m(3)) above which all DD tests were positive. Nevertheless, this threshold volume was too great to include all ST extending to the terminal portion of the saphenous. Measurement of DD level is thus not contributive to the diagnosis of ST.

[Treatment by lepirudin and acenocoumarol of heparin induced thrombocytopenia after valvular surgery: a word of caution]. / Traitement par lépirudine et acénocoumarol d'une thrombopénie induite par l'héparine après chirurgie valvulaire: conseils de prudence.

The diagnosis and treatment of type II heparin-induced thrombocytopenia (HIT) after valvular surgery raise difficult issues due to the substitution of heparin by other anticoagulants. A 50-year-old man with hepatic cirrhosis and acute infective endocarditis underwent aortic valve replacement. On the 4th postoperative day platelet count decreased to 50 g/l. Platelet aggregation was demonstrated in vitro with unfractioned and low molecular weigh heparins and danaparoid sodium. As serum creatinine was 94 micromol/l, lepirudine (r-hirudin) was administered at recommended doses. However, six hours later hirudinaemia estimated by ecarin-clotting time was 3 mg/l and lepirudine dose had to be divided by 15 in order to reach therapeutic levels. Similarly, INR increased up to 6,7 on the 11th postoperative day after acenocoumarol 1 mg daily was administered. Despite the presence of oesophageal, gastric and duodenal lesions at risk of haemorrhage no bleeding was detected. The reasons for overdosage are discussed. The necessity of measurement or calculation of creatinine clearance before lepirudine prescription and frequent hirudinaemia during treatment is emphasized.

[Prevention of venous thromboembolism following cardiac, vascular or thoracic surgery]. / Prévention de la maladie thromboembolique veineuse périopératoire en chirurgie cardiaque, vasculaire et thoracique.

In the absence of thromboprophylaxis, coronary artery bypass graft surgery (CABG), intrathoracic surgery (thoracotomy or video-assisted thoracoscopy), abdominal aortic surgery and infrainguinal vascular surgery are high-risk surgeries for the development of venous thromboembolic events (VTE). The incidence of VTE following surgery of the intrathoracic aorta, carotid endarterectomy or mediastinoscopy is unknown. Data from the litterature are lacking to draw evidence-based recommandations for venous thromboprophylaxis after these three types of surgeries, and the following guidelines are but experts'opinions (Grade D recommendations). Thromboprophylaxis is recommended after CABG (Grade D), with either subcutaneous (SC) low molecular weight heparin (LMWH) or SC or intravenous (i.v.) unfractioned heparin (UH) (PTT target = 1.1-1.5 time control value) (both grade D). This may be combined with the use of intermittent pneumatic compression device (Grade B). After valve surgery. The anticoagulation recommended to prevent valve thrombosis is sufficient in order to prevent VTE. We recommend thromboprophylaxis with either LMWH or low dose UH to prevent VTE after aortic or lower limbs infrainguinal vascular surgery (both grade B and D). Vitamine K antagonists (VKA) are not recommended in this indication (Grade D). We recommend thromprophylaxis following intrathoracic surgery via thoracotomy or videoassisted thoracoscopy (grade C). Either subcutaneous LMWH or subcutaneous or i.v. low dose UH may be used (Grade C). Efficacy of intermittent pneumatic compression device has been demonstrated in a study (grade C). VKA are not recommended (grade D). No further recommendation regarding the duration of thromboprophylaxis after these three types of surgeries can be made.

Two novel fibrinogen variants found in patients with pulmonary embolism and their families.

BACKGROUND: The occurrence of dysfibrinogen is quite rare in comparison with other hemostatic defects, specially in cases of venous thrombosis. OBJECTIVES: Fibrinogen is known to have multiple functions, which are not evaluated by simple coagulation testing. We have used gel electrophoresis to search for new mutations. PATIENTS AND METHODS: Specimens of purified fibrinogen from 217 consecutive patients with familial or recurrent or early thrombosis and from 490 control subjects were evaluated by electrophoresis. Plasma fibrinogen levels and coagulation-dependent tests (electromechanical and optical coagulometric determinations, immunological measurement, thrombin and Reptilase(R) times) were normal. RESULTS: Two novel familial variants were detected. For a 42-year-old patient, an in-frame 117 base pair insertion in the Aalpha-chain gene caused a 5-kDa mobility shift of the Aalpha chain. This corresponds to a 39 amino acid duplication in the connector domain (fibrinogen Champagne au Mont d'Or). This pattern was also found in the patient's mother and child. A second 31-year-old patient presented an extra band under non-reducing conditions, 30 kDa larger than HMW fibrinogen and reacting with antifibrinogen antibodies (fibrinogen Lozanne). A heterozygous 5909A-->G mutation was found on the Bbeta-chain gene leading to heterozygous Bbeta Tyr236--> stop codon. The predicted truncated Bbeta chain could participate in chain assembly. Two family members were also affected, one of whom had suffered early venous thrombosis. CONCLUSIONS: Electrophoretic testing of apparently normal fibrinogens can reveal new variants which may be clinically relevant.

Human plasma fibrinogen measurement derived from activated partial thromboplastin time clot formation.

Prothrombin time-derived measurement of fibrinogen (PTd) has already been described. Activated partial thromboplastin time-derived measurement of fibrinogen (aPTTd) has not yet been clearly defined. Using an MDA II coagulometer (Organon Teknika, Durham, North Carolina, USA), we have therefore compared fibrinogen levels determined with Clauss, PTd, and aPTTd assays and an enzyme immunoassay (EIA) in 172 samples. Of these, 47 were from pre-operative controls, 18 from patients with liver disease, 28 from patients with hyperfibrinogenaemia, 33 from patients treated with vitamin K antagonists, 22 from patients treated with unfractionated heparin and 24 from haemophilic patients. Within the normal range, interassay and intra-assay variations were comparable. For control samples, PTd, aPTTd and Clauss assays were well correlated, without any systematic error. EIA was also correlated but values were slightly higher (mean of difference = 0.24). Pathological samples showed an overestimation of fibrinogen when using PTd measurements in patients treated with vitamin K antagonists, as well as when using aPTTd measurements in patients presenting with factor VIII and factor IX deficiencies. These results indicate that, despite expected financial savings, aPTTd fibrinogen measurements should not be used without restriction. PTd and aPTTd fibrinogen determinations are provided without any additional cost. Their comparison with Clauss fibrinogen results may constitute a validation tool or have additional diagnostic utility (e.g. identifying polymerization abnormalities in case of dissimilar results).

Bcl-2, cell cycle regulatory proteins and corticosensitivity in childhood acute lymphoblastic leukaemia.

The results of treatment in childhood acute lymphoblastic leukemia (ALL) remain incompletely satisfactory because of relapses observed even with high dose chemotherapy. The aim of this study was to evaluate the role of bcl-2 or cell cycle regulatory protein expression in peripheral blood cells before and during the first 48 hours of corticotherapy, and corticosensitivity criteria for predicting relapse and prognosis. Fifty two children presenting with ALL were studied at diagnosis and during the first 48 hours of treatment for the level of cell proliferation by measurement of DNA content, and for expression of several cell proliferation regulatory proteins by Western blot. Two criteria for corticosensitivity were used: 1--the number of blast cells present after seven days of treatment with a threshold at 1 G/L (usual criterion), 2--the D8/D1 blast cell ratio, which is independent of the initial leucocytosis. Relapse in the total patient population or in B-cell ALL could only be predicted by the level of leucocytosis before treatment or by p27kip1 expression during the first 48 hours of treatment. Disease free survival was significantly longer when the D8/D1 blast cell ratio was under the 0.75 quartile in the entire patient population (p = 0.03). Among the proteins analyzed, bcl-2 expression before treatment and p27kip1 expression analyzed after 48 hours of corticotherapy were the sole variables associated with significant differences in disease free survival duration in the entire patient population (p < 0.01 and p = 0.04 respectively) or in the B-cell ALL subgroup (p < 0.01). Comparable results were obtained for the overall survival data. The significance of these results is discussed but such a study on blood blast cells needs to be validated in a larger series.

Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia.

BACKGROUND: The use of cardiopulmonary bypass (CPB) in patients with a history of type II heparin-induced thrombocytopenia (HIT) may be associated with complications related to their anticoagulation management. METHODS: Between January 1997 and December 1999, among 4,850 adults patients who underwent cardiac surgery in our institution, 10 patients presented with preoperative type II HIT. In 4 patients, anticoagulation during CPB was achieved with danaparoid sodium. In 6 other patients, heparin sodium was used after pretreatment with epoprostenol sodium. RESULTS: No significant change in platelet count occurred in any patient. No intraoperative thrombotic complication was encountered. Total postoperative chest drainage ranged from 250 to 1,100 ml in patients pretreated with epoprostenol and 1,700 to 2,470 ml in patients who received danaparoid sodium during CPB (p < 0.05, Mann-Whitney U test). CONCLUSIONS: During CPB, inhibition of platelet aggregation by prostacyclin may be a safe anticoagulation approach in patients with type II HIT.

Role of BCL-2 and cell cycle regulatory proteins for corticosensitivity assessment in childhood acute lymphoblastic leukaemia.

Results of treatment in childhood acute lymphoblastic leukaemia (ALL) remain unsatisfactory because relapses occur even after high-dose chemotherapy. Corticosensitivity is used in numerous therapeutic trials as a prognostic factor for treatment choice. The aim of this study was to evaluate the role of cell cycle regulatory protein expression before and during the first 48 h of corticotherapy for predicting corticosensitivity. Fifty-two children presenting with ALL were studied at diagnosis and during the first 48 h of treatment for cell proliferation and apoptosis level by measurement of DNA content, and for expression of several cell proliferation regulatory proteins by means of Western blot. Glucocorticoids induced a significant decrease in the percentage of cells in S-phase and in CDK1, CDK4 and CDK6 expression and an increase in the percentage of cells in subG1 peak. Two criteria for corticosensitivity were used: (i) the number of blast cells after 7 d of treatment with a threshold at 1 x 109/l (usual criterion), (ii) the J8/J1 blast cell ratio, which is independent from initial leucocytosis. Bcl-2 expression at diagnosis was the best predictive variable for the usual corticosensitivity criterion in B- and T-cell ALL. For the second criterion, in B-cell ALL, p21waf1 expression at diagnosis was the sole (albeit poorly) predictive variable, whereas bcl-2 remained of high interest in T-cell ALL. Interestingly, these proteins, bcl-2 and p21waf1, are associated with prolonged cell lifespan and their increased expression is often linked to poor response to cytotoxic drugs. Such preliminary results call for subsequent studies on large independent sets of T-cell and B-cell lineage ALL in order to confirm the J8/J1 blast cell ratio value as well as the role of bcl-2 and p21waf1 expression in predicting corticosensitivity.

Postmenopause hormone treatment in women with NIDDM or impaired glucose tolerance: the MEDIA randomized clinical trial.

OBJECTIVE: To assess the biological safety of four hormone replacement treatment (HRT) combinations in women with non insulin dependent diabetes mellitus (NIDDM) or impaired glucose tolerance (IGT). SUBJECTS AND METHODS: Randomized, double-blind, placebo-controlled trial to analyze the variation of fibrinogen, factor VII, PAI1, and TG blood levels in women (n=99), with NIDDM or IGT, receiving a 3-month course of either oral oestradiol (1 or 2 mg) combined with Chlormadinone Acetate 5 mg, or transdermal oestradiol 50 microg/24 h in association with Norethisterone Acetate (11.2 or 22.4 mg), or placebo. Follow-up lasted 3 months. RESULTS: Ninety nine patients, mean age 56 years (SD 5), mean diabetes duration 7 years (S.D. 7), mean glycated hemoglobin (7.3%) were enrolled. There was no significant difference between the groups for any of the primary hemostasis criteria (n=77). Triglycerides (TG) variation significantly differed between groups, P=0.01, from -21% in the large patch group, to +22% in the placebo group (n=82). Treatment administration routes did not significantly differ for any of the criteria. There was a significant difference in the total cholesterol variation between groups, from +8.7% in the placebo group to -10.8% in the oral 1 mg group (P=0.001). CONCLUSION: The treatments had no highly deleterious effect in these patients with NIDDM or with IGT. Long-term trials can be performed with such patients, and an hormone treatment can be prescribed to relieve symptoms. Since these patients had a well-controlled NIDDM, results might be different in less well-controlled diabetes. The data do not support the hypothesis of an impaired oestrogen effect in patients with NIDDM.

CDK1 and cyclin A expression is linked to cell proliferation and associated with prognosis in non-Hodgkin's lymphomas.

Cellular proliferation is regulated by several kinasic complexes associating cyclins and their catalytic subunits cyclin-dependent kinases (CDKs). In order to gain insight into the mechanisms underlying proliferation in non-Hodgkin's lymphoma (NHL), we examined the expression of certain cell cycle regulatory proteins normally expressed in lymphoid cells, cyclins A, B, D3 and E and cdk1, 2, 4, and 6. In 70 patients presenting a previously untreated lymphoma, cyclins and CDKs were studied by Western blotting and quantified by densitometry. Flow cytometry study of DNA content was carried out for all patients in order to study cell proliferation and level of ploidy. The results were analysed according to the histological types, the immunological phenotypes of the lymphomas and the outcome of the patients. Cdkl and cyclin A were correlated with the percentage of cells in S and S+G2/M phases, and significantly different according to the grade of malignancy, with the lowest expression in low-, and the highest in high-grade NHL according to the Working Formulation. In B-NHLs, cdk1, cyclin A, as well as cdk2, cyclin D3 and E expression was higher in the aneuploid than in the euploid group. Our results point to some particularities of cell cycle regulation in two lymphoma sub-types: 1) a low expression of cyclin D3 and cdk6 in mantle cell lymphomas and 2) a discrepancy between the high proliferative activity and the level of protein expression in Burkitt's lymphomas. CDK1 and cyclin A showed a significant prognostic value for achievement of complete remission (Cdk 1) and for both disease free (cyclin A) and overall survival (cyclin A and cdk1): low protein level was associated with the best prognosis in B-NHLs. Our results show that differential cell cycle regulating protein expression may be associated with different biological and clinical behaviour of NHLs and confirm the usefulness of the study of cell cycle regulation as a tool for understanding lymphoid malignancies.

Enhanced expression of p16ink4a is associated with a poor prognosis in childhood acute lymphoblastic leukemia.

The tumor suppressor gene p16ink4a is homozygously deleted in numerous T as well as in some B lineage acute lymphoblastic leukemia (ALL). We therefore analyzed the clinical and biological implications of this feature by studying p16ink4a expression in 58 cases of childhood ALL. mRNA and protein were significantly correlated and both appeared more highly expressed in B than in T lineage ALLs: 13 out of the 15 T cell ALLs did not show any p16ink4a expression. The main result of this study is the strong prognostic value of p16ink4a expression. When stratifying the patients in three groups according to p16ink4a expression, we observed in univariate analysis: (1) the shortest disease-free survival for patients presenting a high p16ink4a level; (2) contrasting with the good prognosis in the group of patients expressing p16ink4a at low level; (3) while cases without any expression of the inhibitor were associated with a medium course of the disease (P=0.0165). This prognostic value was confirmed by the multivariate analysis showing therapeutic regimen and p16ink4a protein expression as the only variables retained in the model. A specific metabolic profile related to cellular survival and proliferation was observed in each of the three p16ink4a expression groups. Among the cell cycle-related proteins we analyzed, only p21waf1 bcl-2 and CDK4 were significantly and positively correlated to p16ink4a. Furthermore, CDK6 was also strongly expressed in the group of cases with high p16ink4a level. An enhancement of p16ink4a, p21waf1 and bcl-2 was previously described in prolonged cellular survival, while aging cells showed a decrease in CDK4 expression. The concomitant high expression of the oncogenic protein CDK4 (and of CDK6), we observed, may amplify the leukemic advantage of prolonged lifespan blast cells by favoring cell progression through G1 phase. These data suggest that at least two mechanisms may be associated in the oncogenesis of very aggressive ALLs, ie deregulation of cell multiplication and prolonged blast lifespan.

Thrombolysis with intravenous rtPA in a series of 100 cases of acute carotid territory stroke: determination of etiological, topographic, and radiological outcome factors.

BACKGROUND AND PURPOSE: Although new, large, double-blind, randomized studies are needed to establish the efficiency of intravenous thrombolysis, open trials of sufficient size may also provide novel data concerning specific outcomes after thrombolysis. METHODS: An open study of intravenous rtPA in 100 patients with internal carotid artery (ICA) territory strokes between 20 and 81 years of age, with a baseline Scandinavian Stroke Scale (SSS) score of <48 at entry was conducted. Inclusion time was within 7 hours after stroke onset. rtPA (0.8 mg/kg) was infused for 90 minutes, with an initial 10% bolus. Heparin was given according to 3 consecutive protocols. The SSS evaluation was done on days 0, 1, 7, 30, and 90. CT scan was performed before treatment, on days 1 and 7. Etiological investigations included echocardiography and carotid Doppler sonography and/or angiography. Outcome at 1 year was documented by SSS score, the modified Rankin Scale (mRS) score, and a 10-point invalidity scale. Multivariate logistic regression was used to identify predictors of poor versus good outcome. RESULTS: At day 90, 45 patients (45%) had a good result, defined as complete regression or slight neurological sequelae (mRS score of 0-1), 18 patients had a moderate outcome (mRS 2-3), and 31 patients had serious neurological sequelae (mRS 4-5). Six patients died, 2 with intracerebral hematoma after immediate heparin. Five of 11 patients (45.5%) treated between 6 and 7 hours had a good result. The overall intracerebral hematoma rate was 7%. Higher values of fibrin degradation products at 2 hours were observed in the subgroup with intracerebral hematomas. Significant predictors of poor outcome on multivariate logistic regression analysis were baseline SSS score of <15 (odds ratio [OR], 3.38; 95% confidence interval [CI], 1.07 to 10. 74; P=0.04), indistinction between white and gray matter on CT scan (OR, 6.59; 95% CI, 2.19 to 19.79; P=0.0008), and proximal internal carotid thrombosis (OR, 3.29; 95% CI, 0.99 to 10.95; P=0.05). CONCLUSIONS: Our study confirms the safety of intravenous rtPA at a dose of 0.8 mg/kg and suggests efficacy for this drug even within 7 hours. Outcome and hematoma rates were at least as favorable as for trials of therapy with a 3-hour time window. Subgroups with a poor prognosis include low baseline neurological score, baseline CT changes, and proximal ICA thrombosis. However, approximately 30% of patients with each of these characteristics show a good outcome, so their inclusion in future routine rtPA protocols is still justified.