03-2072R
Extended Methods
Design and methods
Study Design and Participants
The current study is based on data from the Villa Pini Stroke data bank, a prospective hospital-based stroke data bank started in March 1998 in Chieti, Italy.1,2 The original inclusion criteria were a diagnosis of first-ever ischemic stroke within 24 hours before enrollment.1 We restricted our study to the 535 patients included between March 1998 and March 2000, who were free of diseases that might substantially affect their levels of CRP (recent clinical infection, concurrent major renal hepatic or cancerous disease, recent surgery or major trauma, acute osteoarthritis, or inflammatory disease), and who had complete data on BP, CRP levels, and covariates. Additional information on the design of the Villa Pini Stroke data bank has been published elsewhere.1,2 Informed consent was obtained from all patients included or their legal representative. The study was approved by our institutional committee.
Study Measures
Blood Pressure
BP was measured at the entry by a learned nurse. Two measurements were taken on each arm after the patient had been calm and supine for five minutes. The lowest measurements on each arm were averaged to obtain the systolic (SBP) and diastolic (DBP) values that were recorded. The first and fifth Kortokoff sounds were recorded and used to determine SBP and DBP, respectively. Mean arterial pressure (MAP) was calculated as (SBP+2DBP)/3. Pulse pressure (PP) was calculated as SBP-DBP.
C-reactive protein assay
Blood samples were taken at admission, within 24 hours after qualifying stroke. Levels of CRP were determined with a commercially available, high sensitivity, immunonephelometric, latex enhanced assay (Dade Behring). The coefficient of variation ranged from 2.3% to 4.4% for the intra-assay precision and from 2.6% to 5.7% for the inter-assay reproducibility.
Other Study Variables
Other factors included in this study were: age, sex, body mass index, cerebrovascular risk factors (cigarette smoking status, alcohol abuse, hypercholesterolemia, hypertriglyceridemia, diabetes mellitus), cardiovascular comorbidity (arrhythmias and impulse conduction disorders, valvulopathies, left ventricular hypertrophy, coronary heart disease, symptomatic internal carotid stenosis, peripheral arterial disease), stroke subtypes [atherothrombotic, cardioembolic, small-vessel occlusive (lacunar), or undetermined cause], neuroradiological findings (leukoaraiosis, single/multiple infarcts, large/small infarcts, brain oedema, hemorrhagic transformation). Information on current use of antihypertensive medications was also obtained. All definitions are previously given1,2 and definitions of stroke subtypes and neuroradiological findings are summarized in Appendix I.
Statistical Analysis
Differences in proportions were evaluated by c2 analysis, unpaired t test for continuous normally distributed variables, and Mann-Whitney U test for nonnormally distributed variables. Continuous variables are described as mean±SD or median values with 25th and 75th percentiles, according to manner of distribution. Pearson's correlation analysis was performed to assess any relationship between log-normalized levels of CRP and blood pressure at the entry. Analyses were designed to assess the association of BP components (SBP, DBP, MAP, and PP) with CRP levels after adjusting for the other study variables. In our analyses, the BP components and other study factors were independent variables, and CRP was the dependent variable. We analyzed CRP as a dichotomous outcome (CRP <1.5 mg/dL or CRP ³1.5 mg/dL) in logistic regression models. We chose a cutoff point of 1.5 mg/dL because it has provided better sensitivity and specificity for adverse outcome, based on the receiver operator curves in a previous analysis in this stroke cohort,2 thereby ensuring that odds ratios generated from logistic regression models to predict elevated CRP level would be roughly interpretable as relative risks. The regression analyses were performed as follows. The explanatory variables were first tested 1 by 1 against the dependent variable for the presence of a significant association (P<0.05). Variables for which no significant association was found were removed from the model. Individual BP component models assessed the effect of a single BP component (SBP, DBP, MAP or PP) on CRP, without adjustment for other BP components. Dual BP component models assessed the effects of MAP and PP on CRP after adjustment for one of the other BP components (SBP and DBP). A final model assessed the effects of all BP components (SBP, DBP, MAP, and PP) on CRP level. In all of the logistic models, the BP components were entered as continuous, linear variables, and odds ratios for the BP components were calculated per 10 mm Hg increase in the component. Age (per 10 year increase) and Canadian Neurological Stroke Scale Score3 (CNSS) were also entered into the logistic models as continuous variables (per 1.0 point increase). All the other variables were included as categorical variables according to the categories described previously.1,2
Appendix I
Subtypes of categories of ischemic stroke
Atherothrombotic stroke
This category required occlusion or 50% stenosis of the internal carotid artery by carotid ultrasound/duplex studies or 50% stenosis of the carotid, middle, anterior, and/or posterior cerebral, vertebral, or basilar arteries by angiography or magnetic resonance angiography in ³1 plane that is in a vascular distribution consistent with stroke symptoms. Distinction between resolving embolism and primary disease of the intracranial vessel was made by the neuroradiologist.
Cardioembolic stroke
This category includes myocardial infarction within 6 weeks of stroke onset; acute congestive heart failure, mitral stenosis confirmed by clinical examination, echocardiography, or autopsy; artificial heart valve; atrial fibrillation or atrial flutter on ECG; thrombus in the atrium or ventricle or on the aortic or mitral valve identified by echocardiography or coronary angiography; left ventricular aneurysm identified by echocardiography or coronary angiography; and sick sinus syndrome identified by monitoring of cardiac rhythm. Patients with an akinetic or hypokinetic wall segment by echocardiogram also are included.
Small-vessel occlusive (lacunar) stroke
Either condition 1, 2, or 3 is true. In condition 1, brain images show a deep infarct 1.5 cm in its maximal diameter that is appropriate to a clinical classic lacunar syndrome. In condition 2, brain images show no lesion to explain the clinical syndrome, and the clinical presentation is one (including the following) usually associated with a small deep infarct. Pure motor hemiplegia is hemiparesis or hemiplegia involving the face, arm, and leg equally or arm and leg equally without other neurological findings. Although mild sensory symptoms can be present, there is no sensory loss on examination that is related to the infarct. Pure sensory stroke has isolated sensory loss or disturbance involving the entire hemiface and hemibody or the hemibody alone. There may be incidental motor weakness from another cause. Ataxia-hemiparesis is hemiparesis with ipsilateral ataxia. Paresis is more commonly crural. Dysarthria/clumsy hand syndrome is dysarthria with a clumsy hand. Facial weakness is possible. Hemiballismus, hemiathetosis, or hemidystonia must be acute onset. In sensorimotor stroke, there are weakness and sensory loss involving the face, arm, and leg equally without other neurological findings. In condition 3, CT scan shows a deep infarct of 1.5 cm in its maximal diameter that is appropriate to the clinical syndrome, but the syndrome is not 1 of the classic syndromes for lacunar stroke.
Undetermined cause
This category included relatively rapid onset of a major focal neurological deficit that persists >24 hours or is fatal and cannot be attributed to another cause. This category is used when a patient does not meet any of the above criteria.
Other Cause
This category included cerebral infarction caused by another clearly identified cause of stroke (eg, traumatic arterial dissection, post–coronary bypass graft surgery, post–carotid endarterectomy, acquired immune deficiency syndrome, and cocaine use).
Neuroradiological findings
Large/small infarcts
Large infarcts were so designated when the sum of the largest transverse and sagittal diameter divided by 2 was >1.5 cm; small infarcts, when the sum of the largest transverse and sagittal diameter divided by 2 was £1.5 cm.
Cortical involvement
Cortical involvement is defined when cerebral infarction is extended >50% to cortical structures. Cortical structures refers to the gray matter on the exterior of the cerebral hemispheres. Subcortical refers to deeper structures, including corona radiata, basal ganglia, internal capsule, thalamus.
Leukoaraiosis
The presence of diffuse or patchy lucencies of the white matter or centrum ovale.
Hemorrhagic infarction
It is a hemorrhage originating within and secondary to infarction and has a characteristic radiographic appearance that distinguishes it from primary hemorrhage.
Brain swelling
In the presence of mass effect as suggested by complete sylvian fissure obscuration, extensive effacement of the hemisphere, including lateral ventricle compression.
References
1. Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke. 2001;32:133-138.
2. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke. An independent prognostic factor. Stroke. 2001;32:917-924.
3. Cotè R, Battista RN, Wolfson C, Boucher J, Adam J, Hachinski V. The Canadian Neurological Scale: validation and reliability assessment. Neurology. 1989;39:638–643.
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