Selective intra arterial thrombolysis in acute carotid territory stroke.
The safety and efficacy of selective intraarterial administration of urokinase in five male patients, (age range 30 to 65 years, mean 41.2 years), with occlusive stroke involving the carotid territory and a normal cranial computed tomography scan was evaluated. The time elapsed before treatment ranged from one to 10 hours. Digital subtraction angiography disclosed distal internal carotid artery occlusion in one patient and occlusion of the middle cerebral artery or its branches in the others. The urokinase dose ranged from 120,000 to 500,000 units. In two patients who received thrombolytic treatment within three hours of the onset of symptoms, there was a 100% recanalisation associated with excellent neurological recovery. In the remaining three patients, recanalisation rate varied from 0 to 50% with partial recovery in two and no recovery in one patient. None had a haemorrhagic transformation of the infarct. Although no firm conclusions can be drawn because of the small number of patients studied, selective intraarterial urokinase therapy appears to be safe and useful in patients with carotid territory stroke if undertaken early. Only through a multicenter, randomized, controlled trial, enough number of patients can be recruited to verify these observations.
Stroke is a leading cause of disability and death all over the world. Approximately, 75% of strokes are ischaemic, resulting from complete occlusion of an artery that supplies blood to a region of the brain. In developing countries, stroke afflicts people at relatively younger ages., During the past 10 years, active management strategies such as thrombolytic and neuroprotective agents have been shown to influence outcome and are slowly displacing the mood of therapeutic nihilism associated with stroke management.,
Recently, the United States Food and Drug Administration approved intravenous tissue plasminogen activator (t-PA) for use in selected patients with ischaemic stroke based on the positive results of the National Institute of Neurological Disorders and Stroke (NINDS) trial., In the NINDS trial, patients treated with intravenous t-PA within three hours of the onset of stroke were at least 30% more likely to have minimal or no disability at three months compared to those treated with placebo. Although there was a 10-fold increase in the risk of symptomatic intracerebral haemorrhage in the t-PA treated group; this complication did not result in an overall increase in mortality. However, the European Cooperative Acute Stroke Studies I and II with intravenous t-PA and all the three trials with intravenous streptokinase,, did not confirm the results of NINDS trial. The use of intravenous thrombolytic therapy for acute stroke in clinical practice thus remains extremely controversial and debated.,
Recent advances in techniques of intracranial vascular catheterisation have made it possible to deliver thrombolytic agents intraarterially directly proximal to the thrombus with much less systemic side effects.,, A few recent studies have investigated the efficacy and safety of selective intraarterial urokinase administration in patients with carotid, and vertebrobasilar,  occlusive stroke. Barnwell et al recently reported the usefulness of intraarterial urokinase therapy among stroke patients even when they had presented after six hours.
We undertook this study to assess safety, recanalisation frequency and clinical efficacy of selective intraarterial urokinase administration in patients with acute ischaemic stroke in the internal carotid artery territory.
Between June 1996 and February 1997, five patients who presented with symptoms of acute carotid territory stroke were treated with intraarterial urokinase at the Sri Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum. This Indian Medical Council funded research project had the approval of the institutional ethics committee.
Call for patients : We advertised through newspapers and television, and sent communications to all medical practitioners and hospitals in and around the city of Trivandrum to accomplish prompt referral of patients with acute stroke.
Patient selection :Inspite of our best efforts, we could recruit only five patients during the study period, who fulfilled the following inclusion criteria: i) age <65 years; ii) first ever stroke in the carotid territory within the previous 12 hours; iii) no impairment of consciousness; iv) normal cranial computed tomography (CT) scan; v) angiographically demonstrable occlusion in the carotid territory; and vi) blood pressure < 185/110 mm Hg. Patients with minor neurological deficit (motor power, MRC grade >3/5), suspected cardiogenic brain embolism, myocardial infarction or surgery within the previous six months, poorly controlled diabetes mellitus or renal failure, and known bleeding disorders were excluded.
Procedure : A digital substraction angiogram (DSA) was performed via retrograde femoral catheterisation of the common carotid artery of the symptomatic side. Once the site of occlusion was confirmed, a Tracker 18 microcatheter with a 2.7 French tip diameter was navigated into the internal carotid artery or to a more distal vessel and placed as close to the vascular occlusion site as possible. Urokinase in a bolus doses of 25,000 units was administered over 10 minutes into the occluded segment of the vessel just proximal to the occlusion. Selective supraclinoid internal carotid or distal vessel DSA was repeated after urokinase infusion to check the recanalisation. If the recanalisation was not satisfactory, 25,000 units of urokinase infusions were repeated under DSA monitoring. The endpoint of the procedure was either >70% recanalisation, a maximum urokinase dosage of 500,000 units, deterioration in consciousness or hypersensitivity reactions. The extent of recanalisation was classified based on the percentage ratio of vascular area viewed in the lateral DSA before and after the procedure as: complete (100%), partial (>50%) and poor (<50%). CT scans were performed soon after the procedure and again on the 7th day to look for any haemorrhagic transformation of the infarcted area.
Clinical assessment and follow up : A complete neurological assessment was done before and immediately after the thrombolytic therapy, every day for the next one week and at 3 months and 6 months. All patients were monitored in the Neurologic Critical Care Unit for at least 24 hours after the thrombolytic procedure. They received intravenous heparin 5000 units/ 6 hourly for 24 hours and oral aspirin 325 mg daily afterwards.
The demographic and clinical characteristics of the patients are provided in [Table - 1]. All the five patients were males. Their age ranged from 30 to 65 years, mean 41.2 years. The time elapsed before treatment ranged from one to 10 hours, mean 5.5 hours. No patient had initial CT scan abnormalities suggestive of early infarction. DSA disclosed distal internal carotid artery occlusion in one patient [Figure - 1], and occlusion of the middle cerebral artery or its branches in the others. In two patients, in whom angiography could be performed and thrombolytic treatment initiated within 3 hours of onset of symptom there was a 100% recanalisation associated with complete neurological recovery in 1 patient and near total recovery in the other. In remaining 3 patients who received thrombolytic therapy between 6 and 10 hours of stroke onset, the recanalisation rate varied from 0-50%. At 3 months, one patient had no change in neurological status and the other two made a partial recovery.
The urokinase dose ranged from 120,000 to 500,000 units. None of our patients had a haemorrhagic transformation of the infarct. No patient had a blood pressure of >185/110 mm Hg, which required intervention. Two patients had minor complications: one had transient haematuria and the other an abdominal wall haematoma, that resolved uneventfully.
MCA = Middle cerebral artery, R = Right, L = Left.
To our knowledge, this is the first study from India, which investigated the efficacy and safety of selective intraarterial urokinase therapy in patients with acute occlusive stroke. This study, involving patients with internal carotid artery territory stroke, demonstrates four major points.
First, we found that urokinase given proximal to the thrombus by selective catheterisation of the occluded artery produced a high rate of recanalisation. Among our five patients, three (60%) achieved 50% or more recanalisation. Two of our patients who received urokinase therapy within 3 hours of the onset of stroke, had a complete recanalisation of the artery. Among 13 patients treated with selective intraarterial urokinase, Barnwell et al observed successful recanalisation in 10 patients. The Prolyse in acute cerebral thromboembolism (PROACT) trial, a randomised, double blind, multicenter, controlled trial involving patients with middle cerebral artery stroke, compared the safety and recanalisation efficacy among 26 patients who received intraarterial prourokinase with 14 patients who received placebo. The recanalisation rate (57.7% versus 14.3%, p <0.02) among those who received intraarterial pro-urokinase was significantly better.
Second, intraarterial urokinase therapy is safe. None of our patients had a haemorrhagic conversion of the infarct. Systemic complications were mild and transient. Asymptomatic haemorrhagic transformation of the infarct occurred in 2 out of 13 patients treated by this mode of therapy by Barnwell et al. In the PROACT trial, the frequency of brain haemorrhage with neurologic deterioration was not statistically different.
Third, intraarterial urokinase therapy may be safe even when administered after six hours of the stroke onset. We choose to treat three patients who presented between 6 and 10 hours after the onset of stroke related symptoms since they had a normal CT scan. Among the 13 patients treated by intraarterial urokinase by Barnwell et al the time elapsed before treatment ranged from 3.5 to 48 hours (mean 12 hours). It appears that selective intraarterial urokinase therapy can be safely given even after the standard six-hour time window for thrombolytic treatment in those with a normal CT scan. Narrow therapeutic window is the major obstacle to widespread adoption of thrombolytic therapy. As a result, even in the United States, only about a small proportion of the eligible stroke patients are currently receiving intravenous t-PA therapy. Furthermore, compared with intravenous thrombolytic therapy, intraarterial administration has an additional delay of about 1.5 hours related to angiography and selective catheterisation.,
Fourth, intraarterial cerebral thrombolysis seems to be clinically beneficial. Although because of the small number of patients we cannot make any firm conclusions, two of our patients who received the therapy within three hours made an excellent functional recovery. The functional outcome was rated as significantly improved among 9 of the13 (69%) patients treated by Barnwell et al. Although the number of patients in the PROACT trial was too small to establish a statistical significance, there appeared to be a 10% to 12% absolute increase in excellent neurological outcome in the pro-urokinase treated group over placebo at three months.
Our study was intended to compare the outcome of 20 stroke patients treated with intraarterial urokinase therapy with the outcome of 20 stroke patients with angiographically demonstrable occlusion but not treated by thrombolysis. However, in a time period of 20 months we could recruit only five patients. This highlights the problems associated with therapeutic trials in acute stroke in a developing region. A majority of our patients presented to us after considerable time has lapsed between the onset of stroke and CT demonstrable ischaemic lesions have already appeared. This is especially disappointing because Kerala, the state where the study was conducted, is well known for the high level of literacy and health awareness of its population. The need of educating the primary and secondary care physicians and the lay public about the new avenues in stroke therapy and importance of rapid diagnosis and transport to a speciality center cannot be overemphasized., The recent term "brain attack" has heightened the sense of urgency in stroke therapy.
The use of intraarterial thrombolysis in the treatment of vertebrobasilar occlusion has also shown promising results., Only through a multicenter trial, enough number of patients can be recruited to verify these observations. PROACT II trial, a multicenter, phase III, randomized, controlled trial, currently being undertaken to assess the outcome in 180 patients with middle cerebral artery occlusive stroke treated with intraarterial pro-urokinase, may provide more reliable information regarding the efficacy and safety of intraarterial thrombolytic therapy in acute ischaemic stroke.
The major disadvantage of intraarterial thrombolytic therapy is that it can only be undertaken in centers where neurointerventional specialists and infrastructure required for this intervention are available. Furthermore, the administration of a potentially toxic drug by a highly specialized technique to an acutely ill and vulnerable patient within a short time frame demand an expert decision making process after a thorough consideration of the risks and benefits., Because of these reasons, it is unlikely that selective intraarterial thrombolytic therapy will ever produce a significant impact in the treatment of acute ischaemic stroke in a developing country.