Neurology India, Vol. 59, No. 3, May-June, 2011, pp. 351-354
Early outcome after intravenous thrombolysis in patients with acute ischemic stroke
Pornpatr A Dharmasaroja1, Sombat Muengtaweepongsa1, Permphan Dharmasaroja2
1 Department of Internal Medicine, Faculty of Medicine, Thammasat University, Thailand
Correspondence Address: Pornpatr A Dharmasaroja Division of Neurology, Faculty of Medicine, Thammasat University, Klong 1, Klong Luang, Pathumthani 12120 Thailand email@example.com
Date of Submission: 28-Mar-2011
Code Number: ni11108
AbstractBackground : Patients with acute ischemic stroke who had early neurological improvement had better functional outcome. The purpose of this study was to determine factors associated with early clinical improvement and early worsening in patients with acute ischemic stroke treated with intravenous thrombolysis.
Patients and Methods : Patients treated with intravenous recombinant tissue plasminogen activator (rtPA) between August 2008 and November 2010 were the subjects of this study. Early improvement was defined by marked, clinical improvement or complete recovery at 24 h (National Institutes of Health Stroke Scale (NIHSS) 0-4 at 24 h). Early worsening was defined by an increase in NIHSS ≥1 from baseline. The baseline characteristics were compared between patients with and without outcome of interest.
Results : Of the 203 patients studied, 19 (9.4%) patients had complete recovery and 68 (33.5%) patients had marked clinical improvement (NIHSS 1-4) at 24 h. Most patients with early clinical improvement (86%) had favorable outcome at three months. Of the 22 (10.8%) patients who had early clinical worsening, only three (14%) patients achieved favorable outcome at three months and six (29%) patients died. Multivariate analysis revealed that older age (≥70 years old) (odd ratio (OR) 0.498, P = 0.049), severe stroke (NIHSS ≥15) (OR 0.154, P < 0.0001) and having intracerebral hemorrhage (ICH) (OR 0.364, P = 0.032) were inversely associated with early improvement. History of transient ischemic attack (TIA) (OR 7.724, P = 0.043) and ICH (OR 4.477, P = 0.008) were related to early worsening.
Conclusions : The presence of early clinical improvement or worsening within 24 h after treatment with rtPA had major impact on the outcome at three months.
Keywords: Asia, outcome, stroke, Thai, thrombolysis
Intravenous thrombolysis has become a standard treatment in eligible patients with acute ischemic stroke. As compared with patients given placebo, patients who were treated with recombinant tissue plasminogen activator (rtPA) were at least 30% more likely to have a favorable outcome (modified Rankin Scale 0-1) at three months.  Patients with early neurological improvement or recovery had shorter in-hospital time and better functional outcome at three months. , Because information about early outcome after rtPA treatment in Asian patients was scarce, the purpose of this study was to look for the factors associated with early clinical improvement and early worsening in patients with acute ischemic stroke treated with intravenous thrombolysis.
Patients and Methods
Patients who were treated with intravenous thrombolysis between August 2008 and November 2010 were included in the study. Intravenous rtPA (0.9 mg/kg) was prescribed in eligible patients with acute ischemic stroke within 4.5 h after the onset. Informed consent was taken from the patients. Most of the exclusion criteria were similar to the guidelines proposed by the American Heart Association/American Stroke Association.  However, older age (>80 years) was not an exclusion criterion. Patients with high blood pressure (systolic blood pressure (SBP) >185 mmHg or diastolic blood pressure (DBP) >110 mmHg) were not excluded if blood pressure could be controlled by intravenous nicardipine (target SBP <185 mmHg and DBP <110 mmHg) before rtPA administration. Abnormal findings from computed tomography (CT) brain: a) hyperdense lesions, suggestive of bleeding and b) hypodense lesion more than one-third of middle cerebral artery distribution, were also contraindications for thrombolysis. Patients who were treated with intravenous rtPA were admitted to an intensive care unit or stroke unit for monitoring and tight controlling of blood pressure with close clinical follow-up for the first 24 h. Follow-up CT brain was done within 24-36 h after thrombolysis. The severity of the stroke was evaluated by the National Institutes of Health Stroke Scale (NIHSS) before and 24 h after rtPA treatment. Early improvement was defined by clinical improvement or complete recovery at 24 h (with final NIHSS at 24 h 0-4). Early worsening was defined by an increase in NIHSS ≥1 from baseline or before treating with rtPA which could not be explained by other causes, such as sepsis, besides stroke. Modified Rankin scale (mRS) was used to assess the outcome of the patients at three months from the onset of the stroke. Symptomatic intracerebral hemorrhage (ICH) was defined by the National Institute of Neurological Disorders (NINDS) stroke rtPA stroke study criteria, which is hemorrhage associated with worsening of ≥1 point on the NIHSS score. 
Baseline characteristics of patients, including age, gender, cardiovascular risk factors, blood glucose at admission, blood pressure level, platelet count, prothrombin time, severity of stroke, and stroke subtypes were studied. The data was presented as a mean or a median for continuous variables and percentage (number) for dichotomous variables. The demographics and vascular risk factors were compared between patients with and without early improvement/worsening using Student's t test (for the continuous variables) and the Chi-square test (for the proportions). The stepwise multivariate analyses were performed by including the prespecified factors that were associated with measured outcome variables in the univariate analysis. The research protocol was approved by the human ethic committee of Thammasat University Faculty of Medicine.
There were 203 patients treated with intravenous rtPA during the study period. Baseline characteristics of the patients are presented in [Table - 1]. Symptomatic ICH occurred in 11 patients (6.9%). There were 19 (9.4%) patients with complete recovery and 68 (33.5%) patients with marked clinical improvement (NIHSS 1-4 at 24 h). Mean NIHSS scores before and at 24 h after treatment with rtPA were 8 (range from 4 to 30) and 2 (range from 0 to 4), respectively. Twenty-two patients (10.8%) got worse after treatment with rtPA. Mean NIHSS scores before and at 24 h after rtPA in this subgroup were 12 (range from 5 to 24) and 17 (range from 6 to 34), respectively. Reasons for early worsening were symptomatic ICH (11/22 patients, 50%), malignant middle cerebral artery infarction (5/22 patients, 22.7%) and cerebellar infarction (1/22 patients, 4.5%). Four patients who had early worsening had new infarct lesions at the subcortical area, and one at the brainstem.
Fifteen patients had no data about mRS at three months because four patients were lost to follow-up and 11 patients were recently treated with rtPA (less than three months from the data analysis date). Seventy-four (86%) patients with early clinical improvement had favorable outcome (mRS 0-1) at three months, while only three (14%) patients with early worsening had favorable outcome. Six (29%) patients with early worsening died within three months and seven (33%) patients were unable to walk without assistance (mRS 4-5) at three months.
As compared to patients without early clinical improvement, patients with early clinical improvement were younger, had less severe stroke, lower proportion of atrial fibrillation and ICH [Table - 2]. Patients with early worsening had more history of transient ischemic attack (TIA), atrial fibrillation, higher proportion of high blood glucose at the onset and ICH. Multivariate analysis revealed that older age (≥70 years old) (OR 0.498, 95% CI 0.25-0.99, P = 0.049), severe stroke (NIHSS ≥15) (OR 0.154, 95% CI 0.07-0.36, P < 0.0001) and having ICH (OR 0.364, 95% CI 0.15-0.92, P = 0.032) were inversely associated with early improvement [Table - 3]. History of TIA (OR 7.724, 95% CI 1.07-55.99, P = 0.043) and ICH (OR 4.477, 95% CI 1.47-13.64, P=0.008) were related to early worsening.
Early outcome after intravenous thrombolysis had been reported in several studies. However, the definitions of early improvement or worsening used in the studies varied considerably. The rationale in using each definition was not clearly stated. The mechanism of early recovery is not completely understood. A transcranial Doppler (TCD) study in patients treated with rtPA found that the timing of arterial recanalization as determined by TCD correlated with clinical recovery from stroke and demonstrated a 300-min window to achieve early complete recovery.  Early complete recovery (within 24 h) was found in 9.4% (30 out of 320 patients) of the patients in one study.  Patients with complete recovery were younger, more often male, had milder stroke symptoms, less often cardioembolic stroke and fewer bleeding complications. They also had shorter in-hospital time and better functional outcome at three months. Early neurological improvement after rtPA treatment was also reported in 18.3-66.9% with more favorable outcome. ,, In our study, 19 (9.4%) patients had complete clinical recovery and 68 (33.5%) patients had marked improvement at 24 h, which was comparable to the previous studies. Most patients (86%) with marked clinical improvement after intravenous thrombolysis had favorable outcome at three months and none died. Patients with clinical improvement were younger, had less severe stroke and asymptomatic ICH. Multivariate analysis showed that old age (≥70 years old), severe stroke (NIHSS ≥15) and all ICH were inversely associated with early clinical improvement.
Several studies reported secondary worsening of stroke symptoms, 13-37%. ,,,, Early worsening of stroke symptoms most likely results from mechanisms inherent to the infarct, while late worsening more likely results from systemic factors, such as infection.  A few mechanisms have been proposed. Hypoperfusion and distal embolisation can lead to progressive infarction in patients with severe stenosis or occlusion of large arteries and penetrating artery disease. Chronic hypertension impairs microvascular function and blood flow, which likely reduces the potential of the microvasculature to provide collateral circulation to ischemic areas. 
Early clinical worsening was reported in 12-16% of the patients after rtPA treatment. ,, Symptomatic ICH was one of the causes of worsening in 12.4-33.3% of the patients. Persistent occlusion was found in 33.3-50% of these patients. ,, Reocclusion was a cause in 33.3% in one study.  The mechanisms of early clinical worsening in patients who are treated with intravenous rtPA remain unclear. Besides the significant increase in symptomatic ICH following thrombolysis, inability to achieve or sustain vessel patency at the end of rtPA infusion has been found to be the cause in several studies. , Clinical deterioration occurred in some patients with complete recanalization, which may be explained by progressive enlargement of an irreversibly damaged ischemic core that reperfusion may aggravate damage in the regions of moderate ischemia or hemorrhages after the reperfusion. ,,
Twenty-two (11%) patients had early clinical worsening after treatment with rtPA in our study. Major causes of early worsening were symptomatic ICH (11 patients, 50%) and malignant middle cerebral artery infarction (five patients, 22.7%). Only three patients with early worsening had favorable outcome at three months and almost one-third of the patients died. The proportion of patients with early clinical worsening was comparable to previous studies. Symptomatic ICH and history of TIA were associated with early clinical deterioration.
This study emphasized that the occurrence of early clinical improvement or worsening within 24 h after treatment with rtPA had a major impact on the outcome at three months, either the rate of favorable outcome or death. Several factors were associated with early clinical improvement/worsening.
This research was supported by Faculty of Medicine, Thammasat University and the National Research University Project of Thailand Office of Higher Education Commission. Thanks to Urai Kummarg and Thammasat Stroke Team for helping in patient registration. Thanks to Junya Pattaraarchachai for helping in statistical analysis.
Copyright 2011 - Neurology India
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