Rainer Fogelholm

Different Risk Factors for Different Stroke Subtypes Association of Blood Pressure, Cholesterol, and Antioxidants

BACKGROUND AND PURPOSE Blood pressure is an important risk factor for stroke, but the roles of serum total and HDL cholesterol, alpha-tocopherol, and beta-carotene are poorly established. We studied these factors in relation to stroke subtypes. METHODS Male smokers (n=28 519) aged 50 to 69 years without a history of stroke participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a controlled trial to test the effect of alpha-tocopherol and beta-carotene supplementation on cancer. From 1985 to 1993, a total of 1057 men suffered from primary stroke: 85 had subarachnoid hemorrhage; 112, intracerebral hemorrhage; 807, cerebral infarction; and 53, unspecified stroke. RESULTS Systolic blood pressure > or = 160 mm Hg increased the risk of all stroke subtypes 2.5 to 4-fold. Serum total cholesterol was inversely associated with the risk of intracerebral hemorrhage, whereas the risk of cerebral infarction was raised at concentrations > or = 7.0 mmol/L. The risks of subarachnoid hemorrhage and cerebral infarction were lowered with serum HDL cholesterol levels > or = 0.85 mmol/L. Pretrial high serum alpha-tocopherol decreased the risk of intracerebral hemorrhage by half and cerebral infarction by one third, whereas high serum beta-carotene doubled the risk of subarachnoid hemorrhage and decreased that of cerebral infarction by one fifth. CONCLUSIONS The risk factor profiles of stroke subtypes differ, reflecting different etiopathology. Because reducing atherosclerotic diseases, including ischemic stroke, by lowering high serum cholesterol is one of the main targets in public health care, further studies are needed to distinguish subjects with risk of hemorrhagic stroke. The performance of antioxidants needs confirmation from clinical trials.

Prognostic Value and Determinants of First-Day Mean Arterial Pressure in Spontaneous Supratentorial Intracerebral Hemorrhage

BACKGROUND AND PURPOSE The onset of spontaneous intracerebral hemorrhage (ICH) is often accompanied by transient blood pressure (BP) elevation. The prognostic value and the determinants of this BP reaction have not entirely been solved, and the present study was focused on these questions. METHODS From 1985 to 1991 in Central Finland (population, 246,000), a total of 425 patients had first-ever ICH verified by CT or necropsy. The hematoma was supratentorial in 337 patients. Of the 306 patients with supratentorial ICH who had CT, 282 had the BP measured at least once within 24 hours of onset, and they formed the study population. The case notes and CT films were reviewed, and mean arterial pressure (MAP) was calculated from the highest BP reading. RESULTS The fatality rate was high; 43% of the patients were dead within 28 days of onset. Six independent predictors of the 28-day survival were identified by multiple logistic regression; these predictors were consciousness on admission, first-day MAP, subarachnoid spread of the bleed, lateral shift of hemispheral midline structures, admission blood glucose, and vomiting. The MAPs varied between 66.7 and 203.3 mm Hg, and the cutoff points of the MAP quartiles were 118, 132, and 145 mm Hg. Patients in the first three MAP quartiles had relatively fair outcome, with 71%, 65%, and 60%, respectively, alive 28 days after onset. This was in sharp contrast to the fourth quartile, with only 33% surviving the first 28 days (log-rank, P < .0001 to P = .0010). Patients unconscious/ comatose on admission had significantly higher MAPs than did those who were alert or somnolent/disoriented (ANOVA, P = .0079). However, at all levels of consciousness, the 28-day fatality rate increased from the first to the fourth MAP quartile: 69% in the alert, 186% in the somnolent/disoriented, and 45% in the unconscious/comatose patients. Stepwise multiple regression analysis gave four independent predictors of the first-day MAP: hypertension, age (in an inverse fashion), admission blood glucose, and hematoma volume. CONCLUSIONS The most important predictor of the 28-day survival was the level of consciousness on admission, followed by first-day MAP. Hypertension was the most important predictor of the first-day MAP, followed by age, which had an inverse effect on the MAP level. At all levels of consciousness, high first-day MAP (especially if > 145 mm Hg) worsened the 28-day survival rate.

Controlled Trial of α-Tocopherol and β-Carotene Supplements on Stroke Incidence and Mortality in Male Smokers

Abstract —Observational data suggest that diets rich in fruits and vegetables and with high serum levels of antioxidants are associated with decreased incidence and mortality of stroke. We studied the effects of α-tocopherol and β-carotene supplementation. The incidence and mortality of stroke were examined in 28 519 male cigarette smokers aged 50 to 69 years without history of stroke who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study). The daily supplementation was 50 mg α-tocopherol, 20 mg β-carotene, both, or placebo. The median follow-up was 6.0 years. A total of 1057 men suffered from incident stroke: 85 men had subarachnoid hemorrhage; 112, intracerebral hemorrhage; 807, cerebral infarction; and 53, unspecified stroke. Deaths due to stroke within 3 months numbered 38, 50, 65, and 7, respectively (total 160). α-Tocopherol supplementation increased the risk of subarachnoid hemorrhage 50% (95% CI −3% to 132%, P =0.07) but decreased that of cerebral infarction 14% (95% CI −25% to −1%, P =0.03), whereas β-carotene supplementation increased the risk of intracerebral hemorrhage 62% (95% CI 10% to 136%, P =0.01). α-Tocopherol supplementation also increased the risk of fatal subarachnoid hemorrhage 181% (95% CI 37% to 479%, P =0.01). The overall net effects of either supplementation on the incidence and mortality from total stroke were nonsignificant. α-Tocopherol supplementation increases the risk of fatal hemorrhagic strokes but prevents cerebral infarction. The effects may be due to the antiplatelet actions of α-tocopherol. β-Carotene supplementation increases the risk of intracerebral hemorrhage, but no obvious mechanism is available.

A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke.

Background and Purpose A randomized, double‐blind, placebo‐controlled multicenter trial was conducted to test the hypothesis that nimodipine would improve the functional outcome in acute ischemic hemispheric stroke. Methods A total of 350 patients were randomized to nimodipine 120 mg/d PO or matching placebo for 21 days. Randomization was stratified by onset of therapy, age, and stroke severity. Treatment was begun within 48 hours of onset. The patients had neurological evaluation on admission, on days 1, 7, and 21, and at 3 and 12 months. The primary end points were Rankin grade, neurological score, and mobility at 12 months. Results We did not find any differences in the functional outcome between the treatment groups or between the stratified subgroups. We were also unable in post hoc analyses to find any groups of patients who benefited from nimodipine. During the first month and at 3 months the case‐fatality rate was higher in the nimodipine‐treated patients than in those on placebo (P=.004 and P=.030, respectively), but at the 1‐year follow‐up this difference had lost statistical significance. During the first week nimodipine had a statistically significant lowering effect on both systolic (P=.005) and diastolic (P=.013) blood pressure. Conclusions Nimodipine did not improve the functional outcome of acute ischemic hemispheric stroke. The early case‐fatality rate was higher in the nimodipine group, possibly due to the blood pressure‐lowering effect of nimodipine. (Stroke. 1994;25:1348‐1353.)

Admission blood glucose and short term survival in primary intracerebral haemorrhage: a population based study

Background: The role of admission blood glucose level on the prognosis of patients with intracerebral haemorrhage has not been elucidated. Objective: To examine this association on the basis of an epidemiologically representative patient material. Methods: 249 500 people living in the catchment area of the Central Hospital of Central Finland. The diagnosis of ICH was established if verified by cranial computed tomography (CT) or autopsy. Results: Of the 416 patients who fulfilled the diagnostic criteria, 30 died before admission and 386 were admitted to the Central Hospital. All 329 patients (290 nondiabetics and 39 diabetics) with both admission blood glucose and cranial CT data were included in the study. The mean blood glucose level was 10.6 mmol/l for nondiabetics who died on the day of onset, 8.6 mmol/l for those dying during days 1 to 28, and 6.8 mmol/l for the 28 day survivors. The corresponding figures for diabetics were 13.9 mmol/l, 12.5 mmol/l, and 9.3 mmol/l. In both nondiabetics and diabetics, patients who died had significantly higher mean glucose than the 28 day survivors (p<0.0001 versus p = 0.029). However, blood glucose of the surviving diabetics was as high as that of the deceased nondiabetics (9.3 mmol/l versus 9.1 mmol/l). In nondiabetics, admission blood glucose was associated with parameters signifying severe stroke; disturbed consciousness, large haematoma volume and shift of cerebral midline structures, and high admission mean arterial pressure. In logistic regression analysis, high admission blood glucose in nondiabetics was a significant predictor of death during the first 28 days of onset (odds ratio 1.22, 95% CI 1.07 to 1.40). Conclusions: High admission blood glucose predicts increased 28 day case fatality rate in both nondiabetic and diabetic patients with ICH. Because high admission blood glucose was associated with markers of severe stroke, we are inclined to support the stress theory; high admission blood glucose is the result of a serious ICH.

Long term survival after primary intracerebral haemorrhage: a retrospective population based study.

Objectives: To determine the long term survival and predictors of death in patients with primary intracerebral haemorrhage (ICH) in Central Finland. Methods: Data were collected retrospectively on all adult patients with first ever ICH in Central Finland county between September 1985 and December 1991. The survival of all patients at the end of December 2002 was investigated. Kaplan–Meier survival curves were constructed and factors associated with both early (⩽28 days) and late deaths determined. Long term survival was compared with the general Finnish population of the same age and sex distribution. The causes of death were compared with those of the population of Central Finland. Results: 411 patients with first ever ICH were identified, 199 men (mean age 64.9 years) and 212 women (mean age 69.5); 30 died before hospital admission, and 208 (50.6%) within the first 28 days. In Kaplan–Meier analysis, at 16 years the cumulative survival was 3.2% for men and 9.8% for women. The 28 day survivors had a 4.5-fold increased annual risk of dying during the first year after ICH, and 2.2-fold during years 2 to 6. On admission, significant independent predictors of death within the first four weeks were unconsciousness, lateral shift of cerebral midline structures, mean arterial pressure ⩾134 mm Hg, hyperglycaemia, anticoagulant treatment, and ventricular extrasystoles. Predictors of late death for the 28 day survivors were old age, male sex, and heart failure. Conclusions: Primary intracerebral haemorrhage has a poor short and long term outcome. The results emphasise the importance of primary and secondary prevention for ICH.

Factors Delaying Hospital Admission After Acute Stroke

BACKGROUND AND PURPOSE Clinical trials of new drugs that reverse neurological deficits when used in the first hours of stroke onset suggest that early hospital admission is important. We analyzed a database of patients with acute stroke to determine the factors that delay hospital admission. METHODS We analyzed all patients with their first stroke during 1993 in the province of Central Finland (population, 256 000). Patients referred to the Central Hospital, the only tertiary referral hospital in the area, were included in the study. RESULTS Of the patients with first stroke, 363 (79%) were admitted to the Central Hospital. The stroke subtype was confirmed in 356 (98%) patients with CT scan, and the patient population included 272 (75%) with brain infarction, 51 (14%) with intracerebral hemorrhage, and 40 (11%) with subarachnoid hemorrhage. The most important factor associated with a delay in reaching the hospital was the referral pattern. The median delay was 2 hours for patients brought directly to the Central Hospital, 8 hours if a physician at the local health center was consulted, and 47 hours if the patient was first admitted to the health center for observation. Other factors associated with a delay were ischemic stroke and stroke onset in the evening or night or during the weekend. CONCLUSIONS The majority of patients who are candidates for acute stroke trials arrive at the hospital after prolonged delays for multiple reasons. Public and medical personnel education could result in signficant reduction in these delays.

Serum cortisol and outcome of ischemic brain infarction

The predictive value of serum cortisol level on the prognosis in acute brain infarction of the carotid circulation territory was studied in 101 patients younger than 70 years. The levels of 7 a.m. and 7 p.m. serum cortisol were measured initially and at 1 week. All patients underwent a computed cerebral tomography (CT) within 2 days of the onset of symptoms, and a second CT 3 weeks or 3 month later. Serum cortisol values predicted the stroke outcome. Both the 7 a.m. and the 7 p.m. values in the initial and 1-week samples correlated positively with the severity of hemiparesis on the corresponding days. The 7 p.m. values predicted better than the 7 a.m. values the functional outcome and case fatality during the 3 month follow-up. Initially and at 1 week, the median 7 p.m. serum cortisol values were statistically significantly higher in those with frontally extending infarcts than in those with non-frontal infarcts. Both 7 a.m. fasting blood glucose and glycosylated hemoglobin (HbA1c) measurements were taken within 3 days of the onset in 95 cases. The patients were diagnosed to have prestroke normoglycemia (n = 73) and hyperglycemia (n = 22) on the basis of the HbA1c level. A highly significant (P = 0.0001) correlation was demonstrated between the initial 7 p.m. cortisol and 7 a.m. fasting blood glucose values in those with prestroke normoglycemia, suggesting that hyperglycemia during the acute phase of stroke is a stress response.

Blood glucose, glycosylated haemoglobin, and outcome of ischemic brain infarction

From August 1987 through December 1989 all consecutive conscious patients younger than 70 years with a recent (less than 48 h) brain infarction of the carotid territory were prospectively included in the study. Blood samples for fasting blood glucose and glycosylated haemoglobin (HbA1c) were taken after a median delay of 23 h of the onset of symptoms. The severity of hemiparesis was assessed on admission, at 1 week, 3 weeks, and 3 months. The functional outcome was assessed at 3 months. Computed cerebral tomography was performed on admission, and later on at 3 weeks or 3 months. The brain infarct volume was measured from the CTs. The patients were diagnosed to have prestroke normoglycemia (n = 76) and prestroke hyperglycemia (n = 23) on basis of the HbA1c level. The case fatality rate, severity of hemiparesis, functional outcome, and infarct size did not differ between these 2 groups. On the other hand, fasting blood glucose level of the non-diabetics correlated strongly with the severity of hemiparesis and predicted stroke outcome. A statistically significant correlation was observed between blood glucose values and the volumes of cortical infarcts in non-diabetics. Because prestroke blood glucose level, in contrast to post-stroke blood glucose level, did not have any predictive value concerning stroke outcome it is concluded that high fasting blood glucose values after stroke reflect a stress response to a more severe ischemic brain lesion.

Alcohol Consumption and Stroke Incidence in Male Smokers

BACKGROUND Studies on alcohol consumption and incidences of stroke subtypes have suggested distinct dose-response relationships. Blood pressure and HDL cholesterol mediate the effect of alcohol on coronary heart disease, but similar evidence on cerebrovascular diseases is not available. METHODS AND RESULTS We studied the risk of stroke in 26 556 male cigarette smokers 50 to 69 years of age without history of stroke. The men were categorized as nondrinkers, light (</=24 g/d), moderate (25 to 60 g/d), or heavy (>60 g/d) drinkers. A total of 960 men suffered from incident stroke: 83 with subarachnoid and 95 with intracerebral hemorrhage, 733 with cerebral infarction, and 49 with unspecified stroke. The adjusted relative risk of subarachnoid hemorrhage was 1.0 in light drinkers, 1.3 in moderate drinkers, and 1.6 in heavy drinkers compared with nondrinkers. The respective relative risks of intracerebral hemorrhage were 0.8, 0.6, and 1.8; of cerebral infarction, 0.9, 1.2, and 1.5. Systolic blood pressure attenuated the effect of alcohol consumption in all subtypes of stroke, whereas HDL cholesterol strengthened the effect of alcohol in subarachnoid hemorrhage and cerebral infarction but attenuated the effect in intracerebral hemorrhage. CONCLUSIONS Alcohol consumption may have a distinct dose-response relationship within each stroke subtype-linear in subarachnoid hemorrhage, U-shaped in intracerebral hemorrhage, and J-shaped in cerebral infarction-but further studies are warranted. Systolic blood pressure and HDL cholesterol seem to mediate the effect of alcohol on stroke incidence, but evidently additional mechanisms are involved.