Intravenous Administration Of rt-PA Research Articles

Decrease in blood pressure after intravenous administration of urapidil during recombinant tissue plasminogen activator thrombolysis for acute ischemic stroke

Background: In patients who are candidates for IV recombinant tissue plasminogen activator (rtPA) thrombolysis for the treatment of acute ischemic stroke, blood pressure (BP)-lowering therapy is sometimes needed for systolic BP >185 mm Hg or diastolic BP >110 mm Hg. However, there is vast uncertainty regarding the appropriate choice of an antihypertensive agent. Case summary: A 68-year-old Algerian woman (height, 161 cm; weight, 68 kg; body mass index, 26 kg/m 2) was admitted to the Cardiology Unit of Amiens University Hospital, Amiens, France, for the assessment of nonvalvular atrial fibrillation. She was prescribed furosemide 40 mg/d to treat a slight left cardiac insufficiency. On day 10 of admission, the patient developed left-sided weakness. Neurologic examination revealed left hemiparesis. A computed tomography scan of the head showed no abnormality. Approximately 90 minutes after onset of the neurologic deficit, the patient had a BP of 180/100 mm Hg in both arms, an irregular pulse >75 bpm, and normal heart sounds. The patient was transferred to the Neurovascular Unit. There were no cervical or femoral bruits in this patient. During neurologic examination, the patient was alert and showed no signs of major cognitive deficit. The neurologic examination did reveal, however, minor hemisphere syndrome with left spatial neglect. There was a left lower-facial paresis. Motor examination revealed normal bulk with diminished tone in the patient's left arm and leg. Although there were no physical signs of dehydration, laboratory results revealed moderate signs of dehydration (total protein, 91 g/L [indicating proteinemia]; sodium, 147 mmol [indicating hypernatremia]; and elevated hematocrit, 42.0%). Considering the diagnosis of ischemic stroke and the duration of the symptoms (<3 hours), IV rtPA was administered. Approximately 10 minutes after intravenous rtPA administration, the patient's BP was 210/110 mm Hg, and an IV bolus of urapidil (20 mg) was administered. Approximately 2 minutes following urapidil administration, the patient developed neurologic worsening indicated by left-sided hemiplegia. Her BP was 105/60 mm Hg. The IV rtPA was immediately discontinued and volume replacement was started for 20 minutes. IV rtPA was restarted after the patient remained hemodynamically stable (15 minutes after rtPA was restarted). Following intensive physiotherapy, the patient was discharged on anticoagulation with a favorable outcome. At her 6-month follow-up, the patient had fully recovered. Conclusion: We report a probable case of hypotension associated with IV bolus of urapidil administration during rtPA thrombolysis for acute ischemic stroke in an elderly patient also treated with diuretics.

Intravenous thrombolysis in the emergency department for the treatment of acute ischaemic stroke

Background and aims:Thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rt-PA) improves outcome in patients with ischaemic stroke treated within 3 h of symptom onset, but its extended implementation is...

The Argatroban and tPA Stroke Study

ABSTRACTBackground: The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke is related to clot lysis and arterial recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. However, human data on this combination are limited. Design: We report an update of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose escalation, safety, and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 h. After standard dose intravenous rtPA administration, a 100-μg/kg bolus of argatroban followed by infusion of 1 μg/kg per min for 48 h was adjusted to a target partial thromboplastin time of 1.75 times baseline. Results: Twenty patients with middle cerebral artery occlusions (including 13 men) have been enrolled, with a mean ± SD age of 61 ± 13 years. Baseline median National Institute of Health Stroke Scale score was 12.5 (range, 3–25). The mean ± SD time from symptom onset to argatroban bolus administration was 177 ± 56 min. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 2 patients and there was 1 death. Recanalization was complete in 7 patients and partial in another 7, and reocclusion occurred in 4 within 2 h of rtPA bolus administration. Conclusion: The combination of low-dose argatroban and intravenous rtPA may be safe, and produce faster and more complete recanalization, but a larger cohort of patients is required to confirm this pilot study.

Argatroban tPA Stroke Study

The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute stroke is linked to clot lysis and artery recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. There are no human data on this combination. We report the first phase of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose-escalation, safety and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 hours. After standard-dose intravenous rtPA administration, a 100-mug/kg bolus of argatroban followed by infusion of 1 mug/kg per minute for 48 hours was adjusted to a target partial thromboplastin time of 1.75 times that of the control group. Fifteen patients (including 10 men) were enrolled, with a mean +/- SD age of 61 +/- 13 years. All patients had middle cerebral artery occlusions. Baseline median National Institute of Health Stroke Scale score was 14 (range, 4-25). The mean +/- SD time from symptom onset to argatroban bolus administration was 172 +/- 53 minutes. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 1 patient and there was 1 death. Recanalization was complete in 6 patients and partial in another 4, and reocclusion occurred in 3 within 2 hours of rtPA bolus administration. The safety of low-dose argatroban combined with intravenous rtPA may be within acceptable limits, and its efficacy for producing fast and complete recanalization is promising, but a larger cohort of patients is required to confirm these preliminary observations.

発症３時間以内のｒｔ‐ＰＡ静注による血栓溶解療法の転帰と問題点

Clinical outcomes and problems were studied in 18 patients of acute cerebral infarction who underwent thrombolytic therapy by intravenous administration of rt-PA started within 3 hours from onset. 10 patients (55.6%) resulted in modified Rankin Scale 0 or 1 at 3 months after onset. However, the diagnosis of ischemic early sign on the CT image was sometimes difficult, the diagnosis of high intensity area on the diffusion wighted image of MRI was easy. Before the intravenous administration of rt-PA, any ischemic early sign was detected in 3 patients on the CT image, but any high intensity area was detected in 16 patients on the diffusion wighted image of MRI. 8 patients showed neurological improvement during the intravenous administration of rt-PA, but 4 patients showed neurological deterioration again after the intravenous administration of rt-PA. The clinical outcome was poor in patients with main arterial occlusion on MRA such as internal carotid artery, basilar artery or M1 of middle cerebral artery occlusion. The intravenous administration of rt-PA is effective therapy for acute cerebral infarction, but some problems are considered to be resolved for patients' better outcome.

超急性期脳梗塞に対するｒｔ‐ＰＡ投与認可を踏まえて―急性期脳梗塞治療：ｒｔ‐ＰＡ認可後の現状，使用条件，学会主催講習会について―

According to the Japanese Guidelines for the Management of Stroke (2004), the intravenous administration of rt-PA in patients with cerebral infarction in the extreme acute stage was given a Grade A recommendation, although the use of rt-PA had not been approved in Japan at that time.The Japanese Ministry of Health, Labor and Welfare finally approved the use of rt-PA in October, 2005. At that time, the ministry asked the Japan Stroke Society (JSS) to provide advice to doctors about the use of this drug.JSS has presented a series of teaching courses about the proper use of rt-PA, contraindications, and so on. Between Sept 2005 and March 2006, we provided 148 courses throughout Japan, and 8324 doctors attended these courses.Since Oct 2005, between 200 and 300 patients have received rt-PA each month, and the incidences of adverse effects, including intracranial hemorrhage, have been gradually decreasing (see Fig.2).However, several issues remain, including :1. effectiveness in patients with lacunar infarction.2. effectiveness in patients with complete internal carotid artery occlusion.3. effectiveness in patients at 3 to 6 hours after onset.4. is major hemorrhage more likely in certain categories of patients?5. preferred administration route-intravenous or intraarterial?6. optimal dose of rt-PA in Japanese patients.

超急性期脳梗塞におけるｒｔ‐ＰＡ静注療法適応について―後ろ向き検討によるシミュレーション―

Background and Purpose:Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) within 3 hours after onset of cerebral ischemia was approved in Japan in October 2005. Preceding using rt-PA for acute cerebral infarction, we built a simulation model of patient flow using inpatient data and clarified issues of in-hospital systems.Methods:We retrospectively analyzed consecutive 485 patients with acute ischemic stroke admitted in our center from May 2002 to October 2005. We analyzed the patients who arrived at our center within 120 minutes after the onset, because at least 60 minutes by the admission will be required for evaluating of patient status and informed consent. We estimate the ratio of patients who fulfilled inclusion criteria for intravenous administration of rt-PA in the patients with acute ischemic stroke. We also assessed interval from the arrival to the admission in these patients and factors related to the interval.Results:There were 148 patients (30.5%) who arrived at our center within 120 minutes after the onset of symptoms. There were 94 men and 54 women. Age was 73.9±10.0 years-old (Mean±SD). The time from the onset to the arrival was 78.8±39.8 minutes. Baseline National Institutes of Health Stroke Scale (NIHSS) was 12.4±9.6. In these patients, only 32 patients (21.6%) fulfilled criteria for the inclusion prior to the admission. The remaining patients were excluded due to the following reasons:unknown onset time, 55; regression of symptoms, 11; mild symptom (NIHSS54), 47; history of intracranial hemorrhage, 3;convulsion, 3; extensive early CT sign, 35 and other reasons, 8. In the included 32 patients, five patients needed more than 180 minutes from the onset to the admission. Finally, 27 patients (5.6% in the all patients) admitted within 180 minutes after the onset and fulfilled the inclusion criteria. In 148 patients, 81 patients were not admitted within 60 minutes after the arrival. Sixty-seven patients were admitted within 60 minutes after the arrival and had significant higher NIHSS than those admitted more than 60 minutes. Age, referral hospital, ambulance or arrival time was not significant factor for the interval from the arrival to the admission.Conclusion: We estimated the candidate for acute thrombolysis using intravenous rt-PA to be 5.6% of total patients with acute ischemic stroke. Patient evaluation frequently required more than 60 minutes prior to the admission, even if the patients arrived at our center within 120 minutes after the onset. We should establish the in-hospital system to reduce the time for patient evaluation.

Effects of recombinant tissue plasminogen activator after intraluminal thread occlusion in mice: role of hemodynamic alterations.

It has been suggested that recombinant tissue plasminogen activator (rtPA) may cause an aggravation of injury after transient focal ischemia via excitotoxic side effects. Such rtPA toxicity would be of major clinical significance since rtPA is increasingly used in stroke treatment. This study was conducted to evaluate the effects of dose, application time, and hemodynamic changes after intravenous rtPA treatment in focal ischemia. Mice were subjected to a 90-minute episode of middle cerebral artery thread occlusion, and rtPA effects were assessed by laser-Doppler flowmetry, [(14)C]iodoantipyrine autoradiography, and triphenyltetrazolium chloride staining. We provide evidence that rtPA provokes complex hemodynamic alterations in the ischemic brain tissue, which include an initial hyperperfusion and a more delayed hypoperfusion response. Changes are most pronounced in the periphery of the ischemic infarct, where regional blood flow drops below critical thresholds of tissue viability. Our observations suggest that changes of perfusion may at least partly explain the rtPA-induced increase of infarct size, which has previously been reported and which we also confirmed in the present experiments. Notably, both the secondary hypoperfusion and increase of infarct volume were abolished when rtPA-treated animals received additional heparin infusions. This finding suggests that a secondary hypercoagulability may compromise brain perfusion after rtPA delivery. Accordingly, early treatment with heparin might help to prevent the rtPA-induced changes.

Early spontaneous intermittent myocardial reperfusion during acute myocardial infarction is associated with augmented thrombogenic activity and less myocardial damage

This study investigated the influence of early spontaneous intermittent reperfusion on the extent of myocardial damage and its relation to endogenous hemostatic activity. In the early phase of acute myocardial infarction coronary occlusion is often intermittent, even before thrombolytic therapy is administered. The relation between this phenomenon, myocardial damage and hemostatic activity is unknown. Holter ST segment recording and pretreatment plasma tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1) antigen, prothrombin fragment F1 + 2 and soluble fibrin levels were measured in 57 patients with acute evolving myocardial infarction. Spontaneous intermittent myocardial reperfusion, defined as two or more episodes of transient resolution of ST segment elevation to within 0.05 mV of baseline, lasting > or = 1 min, before the start of recombinant t-PA (rt-PA) treatment was present in 28 patients (group 1) and absent in 29 (group 2). Left ventriculography and coronary angiography were performed 90 min after intravenous rt-PA administration. Plasma creatine kinase-MB fraction (CK-MB) levels were measured every 6 h for 24 h, and C-reactive protein levels were measured daily for 3 days. Group 1 had lower peak plasma CK-MB (141.9 +/- 28.3 vs. 203.8 +/- 23.3 IU/liter [mean +/- SEM], p < 0.014) and C-reactive protein levels (16 +/- 4 vs. 28 +/- 4 mg/liter on day 1; 26.6 +/- 5.5 vs. 61.8 +/- 14.4 mg/liter on day 2; 19.6 +/- 4.2 vs. 40.6 +/- 6.5 mg/liter on day 3, p < 0.012) and a higher left ventricular ejection fraction (62.9 +/- 4% vs. 51.1 +/- 5%, p < 0.04) than group 2. Group 1 had lower plasma t-PA antigen levels (15.6 vs. 27 micrograms/liter, p < 0.006) but higher prothrombin fragment F1 + 2 (1.8 vs. 1.1 nmol/liter, p < 0.003) and soluble fibrin levels (66.8 vs. 31 nmol/liter, p < 0.01). Coronary patency at 90 min was similar. Early spontaneous intermittent reperfusion during acute myocardial infarction is associated with augmented thrombogenic activity and less subsequent myocardial damage. This finding is consistent with a protective effect of intermittency on the myocardium and a procoagulant effect of spontaneous lysis on blood. It may also reflect a different rate of evolution of coronary thrombosis and myocardial infarction in patients with and those without spontaneous intermittent myocardial reperfusion.

Intraaortic balloon counterpulsation enhances coronary thrombolysis induced by intravenous administration of a thrombolytic agent

Objectives. The study was designed to test the hypothesis that in the presence of moderate hypotension, intraaortic balloon counterpulsation would enhance coronary thrombolysis induced by intravenous administration of recombinant tissue-type plasminogen activator (rt-PA).Background. Although many studies have confirmed the efficacy of thrombolytic therapy in acute myocardial infarction, few pressure on coronary thrombolysis, and none have previously investigated the effects of intraaortic balloon counterpulsation on thrombolysis.Methods. The effects of intraaortic balloon counterpulsation on aortic pressure, coronary blood flow and coronary thrombolysis were studied in a canine model. Coronary thrombosis was induced in eight dogs by injection of radioactive blood clot through a catheter placed in the left anterior descending coronary artery. Subsequently, dogs underwent phlebotomy to decrease systolic aortic pressure to ~90 mm Hg. After phlebotomy, during a 15-min interval of intravenous administration of rt-PA, coronary thrombolysis and coronary flow were determined during and in the absence of counterpulsation.Results. Intraaortic balloon counterpulsation significantly increased aortic diastolic pressure. Corresponding to the increase in pressure, intraaortic balloon counterpulsation significantly increased the rate of rt-PA-induced coronary thrombolysis. Although not statistically significant, peak diastollic coronary flow tended to increase with counterpulsation.Conclusions. These results indicate that in the presence of moderate systemic hypotension, intraaortic balloon counterpulsation enhances the rate of rt-PA-induced coronary thrombolysis.

Reocclusion after thrombolysis

The effect of recombinant hirudin (r-hir), unfractionated heparin (UFH) and acetylsalicylic acid (ASA) on the incidence of reocclusion after thrombolysis with plasminogen activator (rt-PA) was evaluated in anaesthetized rabbits. Formation of a platelet rich thrombus was achieved by implantation of a copper coil into the iliac artery. The occluded artery was recanalized in six of ten animals by intravenous administration of rt-PA given as a bolus injection of 0.1 mg/kg followed by infusion of 0.5 mg/kg/h. Within 1 h after termination of rt-PA infusion rethrombosis was observed in 100% of recanalized vessels. The incidence of reocclusion was diminished by r-hir in a dose-dependent manner to 50% after infusion of 0.05 mg/kg/h and to 25% after 0.1 mg/kg/h. No effect on APTT was detectable in this dosage after 3 h infusion. UFH in a dosage increasing APTT two-fold (35 U/kg/h) did not reduce the reocclusion rate. 100 U/kg/h UFH increased APTT to greater than 3 min and reduced reocclusion rates to 50%. ASA showed a minor effect on the incidence of restenosis whereas the combination of 0.1 mg/kg/h r-hir plus bolus injection of 10 mg/kg ASA led to a further reduction in reocclusion rates to only 11% and an increase in reperfusion rates from 60 to 90%. Our experiments indicate that the combination of plasminogen activator with r-hir may be a useful approach for the prophylaxis of early reocclusion.

Antiplatelet antibody [7E3 F(ab')2] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model.

Coronary artery rethrombosis can complicate initially effective thrombolytic therapy. Platelets interacting with injured vascular endothelium in a region along the coronary artery with reduced luminal cross-sectional area contribute to rethrombosis. The purpose of this study was to investigate the potential of the F(ab')2 fragment of the murine monoclonal antibody 7E3 [7E3 F(ab')2] to prevent rethrombosis after intracoronary clot lysis with recombinant tissue-type plasminogen activator (rt-PA) in an experimental model. The 7E3 F(ab')2 binds to the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), thereby preventing platelet-fibrinogen interaction and intravascular thrombus formation. Experimental coronary artery thrombosis was produced in the anesthetized dog by application of direct anodal current to the intimal surface of the left circumflex coronary artery in the region of an external stenosis. Lysis of the established intracoronary thrombus was achieved with the intravenous administration of rt-PA (25 mg) after which the animals were randomized into two groups. Group 1 (n = 10) served as the control, receiving the saline diluent, and group 2 (n = 9) received 7E3 F(ab')2, given as a single intravenous injection (0.8 mg/kg). The times required for occlusive thrombus formation, rt-PA-induced thrombolysis, and rethrombosis (if it occurred) were similar in the animals treated with saline and those treated with 7E3 F(ab')2. The initial left circumflex coronary artery blood flow was similar in both groups but decreased to a negligible level in group 1. In group 2, left circumflex coronary artery blood flow declined modestly (24 +/- 2 to 10 +/- 2 ml/min). Rethrombosis occurred in all animals in group 1 but in only two of nine animals in group 2 (p less than 0.05). Oscillations in coronary blood flow preceded rethrombosis in group 1, whereas 7E3 F(ab')2 stabilized left circumflex coronary artery blood flow patterns during the course of teh experimental protocol (5.2 +/- 0.9 vs. 0.7 +/- 0.4 oscillations, respectively; p less than 0.05). Thrombus mass recovered from the left circumflex coronary artery at the conclusion of each experiment was greater in group 1 as compared with group 2 (7.0 +/- 2.3 vs. 1.5 +/- 0.7 mg, respectively; p less than 0.05). The area of left ventricle at risk for infarction was similar in both groups but infarct size, infarction/at risk assessed histochemically, was larger in group 1 than group 2 (35 +/- 9% vs. 6 +/- 4%, respectively; p less than 0.05). Platelet aggregation induced by ADP and arachidonic acid was similar at baseline for all of the animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Myocardial tissue salvage by coronary thrombolysis with rt-PA: Absence of occlusion/reperfusion injury

The effect of recombinant tissue-type plasminogen activator (rt-PA) on myocardial infarct size was studied in a coronary thrombosis model in open-chested, anaesthetised beagle dogs. Myocardial ischaemia was produced by localised thrombosis via endothelial injury and instillation of thrombin and fresh blood into the left anterior descending coronary artery (LAD). Myocardial infarct size and the area at risk were determined histochemically after 24 h of reperfusion by ex vivo staining of the LAD bed with 1.5% triphenyltetrazolium chloride (TTC). In non-reperfused animals the persistance of a coronary thrombus resulted in 50.7 ± 5.0% of the area at risk developing an infarct. Intravenous administration of rt-PA at a rate of 12 500 IU/kg/min delivered for 60 min resulted in recanalisation of the thrombosed artery within 16.1 ± 4.1 min in animals in which the thrombus was in place for 75 min and within 19.0 ± 2.8 min after 165 min of stable thrombosis. Lysis of the coronary thrombus and subsequent reperfusion was not accompanied by reactive hyperaemia nor ventricular arrhythmias. Infarct size was reduced to 1.5 ± 1.2% and 6.3 ± 4.1% of the area at risk in the animals whose coronary thrombi were lysed with rt-PA after 1.5 and 3 h of ischaemia, respectively. In contrast, mechanical reperfusion after 1.5 h of ischaemia induced by ligation resulted in an infarct of 35.1 ± 4.5% of the area at risk. These results suggest that rt-PA has an additional cardioprotective effect independent of lysis of the thrombosed coronary artery.