Original Paper

Cerebrovasc Dis 2007;24:196201 DOI: 10.1159/000104477

Received: November 20, 2006 Accepted: February 26, 2007 Published online: June 27, 2007

Hypertensive Intracerebral Hemorrhage in the Very Elderly

Erwin Chiquete a, b M. Carmen Ruiz-Sandoval a, b Luca E. lvarez-Palazuelos a Juan J. Padilla-Martnez a Salvador Gonzlez-Cornejo a Jos L. Ruiz-Sandoval a, b
Department of Neurology and Neurosurgery, Hospital Civil de Guadalajara Fray Antonio Alcalde, and Department of Neurosciences, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mxico
b a

Key Words Aging, hypertension Hypertension, elderly Intracerebral hemorrhage, outcome

Abstract Background: The number of persons reaching the age 80 years and over is increasing in most populations. Literature focusing on hypertensive intracerebral hemorrhage (ICH) in this age group is lacking. Therefore, we aimed to analyze the main clinical characteristics of ICH of the advanced old age, in the context of hypertension. Methods: From 1999 to 2003 we studied 56 hypertensive very elderly patients presenting with ICH (50% women; age 8099 years). As controls, 168 hypertensive gender-matched persons with ICH, aged !80 years, were randomly selected by a 3: 1 factor for clinical comparisons. Results: Compared with their younger counterparts, the very elderly patients had a trend for fewer cases of obesity (34 vs. 49%, p = 0.05) and diabetes mellitus (12 vs. 24%, p = 0.06), had lower systolic, diastolic and mean blood pressure measures (in all, p ! 0.01) and more cases with hematoma extension into ventricles (p = 0.02). Thalamic hemorrhage was more frequent in the very elderly patients than in controls (43 vs. 28%, p = 0.04). In multivariate analysis, age, Glasgow coma scale score at hospital admission, ICH volume and infratentorial location were independent predictors of inhospital mortality, in all persons combined. In the very el-

derly group exclusively, Glasgow coma scale score was the only factor independently associated with mortality. Conclusions: ICH occurring in hypertensive patients aged 680 years has several differences from that seen in younger people; however, these differences do not seem to impact on early outcome. Copyright 2007 S. Karger AG, Basel

Introduction

Advances in science have contributed to the increase in longevity of the world population, a factor that determines the growth of the elderly subgroup [1]. For the last decades, chronic diseases formerly causing death more frequently in middle-aged persons have increasingly been seen in the elderly. As age increases, so does the risk for hypertension [2], which is the single most important modifiable risk factor for intracerebral hemorrhage (ICH) [38]. Scientific reports on ICH of the elderly commonly set an age limit at some point between 55 and 75 years [811]; however, little is known about whether the octogenarian patients with ICH share the same clinical characteristics with younger persons [12]. Furthermore, specific information on hypertension-associated ICH of the very elderly is practically absent in the medical literature.
Dr. Jos Luis Ruiz-Sandoval Servicio de Neurologa y Neurociruga, Hospital Civil de Guadalajara Fray Antonio Alcalde, Hospital 278, Col. El Retiro, Torre de Especialidades, piso 8 Guadalajara, Jalisco CP 44280 (Mxico) Tel. +52 33 3613 4016, Fax +52 33 3614 1121, E-Mail jorusan@mexis.com

2007 S. Karger AG, Basel 10159770/07/02430196$23.50/0 Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/ced

We attempted to provide further information on hypertension-associated ICH of the people aged 680 years, regarding their blood pressure profile, common risk factors, hemorrhage topography and outcome. Our hypothesis was that ICH of the very elderly people is not necessarily equal to that seen at younger ages, in the context of established hypertension.

Methods
From March 1999 to September 2003, unselected consecutive patients with acute symptomatic ICH were prospectively included in the stroke registry database of the Hospital Civil de Guadalajara Fray Antonio Alcalde (Guadalajara, Jalisco, Mexico) [8, 13]. A standardized, structured questionnaire was used to collect data from the caregiver or patient if possible regarding demography, relevant antecedents and current event. A total of 83 consecutive patients with primary ICH, aged 680 years, were studied. Of the 83 very elderly patients registered, we analyzed 56 (67%) persons with a medical history of hypertension. For the purposes of this study, hypertensive ICH was defined as the case of a brain parenchymal hematoma associated with established hypertension, in the absence of other evident etiologies, like head trauma, anticoagulant use and other causes. Cases presenting with a first ICH of lobar location were not ruled out for definite diagnosis of amyloid angiopathy by means of cerebral biopsy. To identify possible age-related clinical differences in ICH location and outcome, 168 gender-matched persons with hypertension-associated ICH, aged !80 years, were randomly selected by a factor of 3:1 from the same database. The internal committee of ethics of our center approved this study. Informed consent was obtained from all patients or their closest relatives. In all cases included, ICH was defined as a sudden focal neurological deficit with intraparenchymal hemorrhage seen on head computed tomography (CT). Hypertensive status was defined as the patient history of hypertension with or without medication. Blood pressure readings (in millimeters Hg) obtained at presentation to the Emergency Department were considered for analyses to evaluate the discrete point of evolution of the ICH in which the first clinical evaluations and decisions were performed. Mean arterial pressure (MAP) was calculated from the systolic and diastolic blood pressure (SBP and DBP, respectively) measurements on admittance to the Emergency Department as follows: MAP = DBP + 0.412 (SBP DBP) [14]. This formula corrects for the spurious variance of calculated MAP seen in individuals with hypertension, when estimated with other formulas [15]. ICH volume (in cubic centimeters) was calculated by analysis of CT scans according to the ABC/2 method, in which A is the greatest diameter on the largest hemorrhage slice, B is the diameter perpendicular to A, and C is the number of axial slices with hemorrhage multiplied by the slice thickness [14]. Obesity was defined as a body mass index 630, smoking habit as the consumption of an average of 65 cigarettes for at least 2 days per week during 612 months and alcoholism as an average of 12 alcoholic drinks per day. Pearson 2 and Fisher exact tests were used to assess proportions in nominal variables for bivariate and homogeneity (when 62 variables) analyses. To compare quantitative variables be-

tween 2 groups, Student t test and Mann-Whitney U test were performed in distributions of parametric and nonparametric variables, respectively. Pearson correlation was used in continuous variables. To find independent predictors of inhospital mortality, multivariate analyses were constructed by forward stepwise logistic regression, for all patients and for the very elderly and the younger controls separately. Adjusted odds ratios with the respective 95% confidence intervals are provided. The fitness of the models was evaluated by the Hosmer-Lemeshow goodness-of-fit test, which was considered reliable if p 1 0.2. All p values are 2sided and considered significant when p ! 0.05. SPSS version 13.0 for Windows (SPSS Inc., Chicago, Ill., USA) was used in all calculations, as well as in the process of randomization and selection of the control group.

Results

We studied 224 hypertensive persons with ICH, 56 elderly patients aged 680 years and 168 gender-matched controls aged !80 years (table 1). Twenty patients (36%) were 185 years old. Fewer cases with obesity (34 vs. 49%, p = 0.05) and diabetes mellitus (12 vs. 24%, p = 0.06) were observed among the elders than in younger controls; however, these differences did not reach statistical significance. All blood pressure measures were significantly lower among the very elderly patients than in controls (in all, p ! 0.01), and even though the ICH volume was not different between groups, extension of the hematoma into the ventricular system occurred more frequently among the patients aged 680 years than in their counterparts (p = 0.02). Also notably, history of previous ICH was not different between both groups (table 1). We could not find any correlation between hematoma size and blood pressure readings for any group; nevertheless, ICH volume inversely correlated with Glasgow coma scale (GCS) score at hospital presentation in both the very elderly (r = 0.652, p ! 0.001) and younger individuals (r = 0.457, p ! 0.001), as could be expected. Overall, the ICH topography did not differ between the 2 study groups; however, thalamic hemorrhages were more frequent among the very elderly patients than in controls (fig. 1). Duration of the hospital stay had a median of 9 days (8 vs. 10 days in the very elderly patients and controls, respectively; p = 0.35), and the inhospital mortality rate was 48% (57 vs. 45% in the very elderly patients and controls, respectively; p = 0.10). A nonneurological cause of death (mainly hospital-acquired pneumonia) occurred in 50% of the cases (53 vs. 49% in the very elderly patients and controls, respectively; p = 0.72). To clarify whether the variables resulting in differences between the 2 study groups impact on in-hospital mortalCerebrovasc Dis 2007;24:196201

Hypertensive ICH in Octogenarians

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50

p = 0.04

Homogeneity, p = 0.27

40

Frequency (%)

30

20

10

Fig. 1. ICH location in patients aged 680

Brain stem

Cerebellum

Thalamus

Putamen

Caudate

Lobes

years (black bars) and younger persons (white bars).

ICH location

Table 1. Risk factors and clinical characteristics of the very elderly patients and gender-matched controls with hypertensive ICH

Variables

All patients (n = 224)

Persons aged 80 years (n = 56) 83 [8099] 19 (34) 6 (11) 9 (16) 7 (12) 2 (4) 9 (16) 158.5827.6 95.2818.1 121.3820.1 11 [415] 8 [182] 15.5 [1160] 39 (70) 24 (43)

Persons aged <80 years (n = 168) 63 [2779] 82 (49) 18 (11) 32 (19) 41 (24) 3 (2) 23 (14) 178.7834.4 103.8817.0 134.7822.4 12 [315] 10 [170] 20 [2160] 88 (52) 72 (43)

p value

Median age, years Risk factors Obesity Alcoholism Current smoking habit Diabetes mellitus Cardiac events Previous ICH Blood pressure profile at hospital admission Mean SBP 8 SD, mm Hg Mean DBP 8 SD, mm Hg Mean MAP 8 SD, mm Hg Median GCS score at hospital admission Median duration of hospitalization, days ICH characteristics Median volume, cm3 Irruption into ventricles Surgical treatment

57 [1899] 101 (45) 24 (11) 41 (18) 48 (21) 5 (2) 32 (14) 173.8833.9 101.7817.6 131.4822.5 11 [315] 9 [182] 20 [1160] 127 (57) 96 (43)

<0.001 0.05 1 0.62 0.06 0.43 0.66 <0.001 0.006 <0.001 0.20 0.35 0.58 0.02 1

Figures in parentheses are percentages and values in square brackets represent ranges. GCS = Glasgow coma scale; SD = standard deviation. p value for differences between patients aged 80 years and younger persons; Pearson 2, Fisher exact test, Student t test (for means) or Mann-Whitney U test (for medians), as appropriate. Surgical treatment: hematoma evacuation with or without ventriculostomy.

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Table 2. Inhospital mortality in relation to differences in the blood pressure profile and ICH topography, in the

very elderly patients and gender-matched controls with hypertensive ICH Variables All patients Persons aged 80 years 32 (57) 0 (0) 4 (12) 10 (31) 6 (19) 1 (3) 7 (23) 27 (84) 157.7 (32.1) 91.7 (20.1) 118.9 (23.2) Persons aged <80 years 75 (45) 9 (12) 6 (8) 18 (24) 11 (15) 1 (1) 7 (9) 52 (69) 185.6 (35.9) 105.5 (16.7) 138.5 (23.4) p value 0.10 0.04 0.46 0.43 0.60 0.53 0.08 0.10 0.001 0.004 0.001

Inhospital mortality 107 (48) Inhospital mortality by ICH location1 Brain stem 9 (8) Cerebellum 10 (9) Thalamus 28 (26) Putamen 17 (16) Caudate 2 (2) Lobes 14 (13) Inhospital mortality and irruption to ventricles2 Ventricular extension present 79 (74) Inhospital mortality and blood pressure3 Mean SBP 8 SD, mm Hg 177.7836.9 Mean DBP 8 SD, mm Hg 101.6818.7 Mean MAP 8 SD, mm Hg 132.9824.8

Figures in parentheses are percentages. SD = Standard deviation. p value for differences between patients aged 80 years and younger persons; Pearson 2, Fisher exact test or Student t test, as appropriate. 1 Location of hematomas in the patients who died in hospital. 2 Presence of extension to ventricles in the patients who died in hospital. 3 Mean blood pressure measures in the patients who died in hospital.

Table 3. Determinants of inhospital mortality: three binary logistic regression models

Variables

Multivariate odds ratios all patients persons aged 80 years NS 0.66 (0.500.86) NS NS persons aged <80 years 1.06 (1.011.10) 0.58 (0.490.70) 1.03 (1.011.05) 6.28 (1.4926.4)

Age GCS score at hospital admission ICH volume ICH in infratentorial location

1.05 (1.021.08) 0.61 (0.520.75) 1.03 (1.011.05) 7.47 (2.2025.30)

Figures in parentheses are 95% confidence intervals. NS = Nonsignificant variable, hence, not appearing as predictor after multivariate analysis. Hosmer-Lemeshow test for goodness of fit in final step of the regression model. Only variables significantly associated with mortality are shown. All patients: 2 = 4.38, d.f. = 8, p = 0.63. Persons aged 80 years: 2 = 4.90, d.f. = 6, p = 0.77. Persons aged <80 years: 2 = 4.76, d.f. = 8, p = 0.78.

ity, we analyzed the ICH topography and blood pressure measures among the patients who died in the hospital, according to the respective age group (table 2). Except for the brain stem location of ICH and the blood pressure readings, no differences were found suggesting a clear impact on inhospital mortality. In any case, the observed differences favored the very elderly group (i.e. the blood pressure profile was less severe and no brain stem locations were found in persons aged 680 years).
Hypertensive ICH in Octogenarians

Multivariate analyses were performed to find independent predictors of inhospital mortality, among the very elderly patients, younger controls and all patients combined (table 3). Age, GCS score at hospital admission, ICH volume and infratentorial location of the hematoma were independent factors associated with inhospital mortality in all patients combined and in persons aged !80 years separately. In the very elderly group, only GCS score at hospital admission was inversely associated with mortality.
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Discussion

The very elderly represent the fastest growing subgroup of the world population [1]. Hence, there is an urgent need for scientific information on common chronicdegenerative diseases in this particular group of people [12, 16, 17]. To the best of our knowledge, this is the first study that examines the characteristics of hypertensionassociated ICH in people aged 680 years. We observed several differences in hypertensive ICH occurring in very elderly persons, as compared with their younger counterparts. At admission to the emergency room, the very elderly patients had lower blood pressure readings than the younger patients, which might be due to a distinct pattern of hypertension of the very elderly [18], to a healthier risk profile or to a different autonomic response to the brain damage [19, 20], issues that deserve more exploration. Brain hematomas located in the thalamus were more frequent among the very elderly than in younger persons, an intriguing finding not previously reported for the hypertensive very elderly patients. This observation should be confirmed with a larger cohort which includes a detailed classification based on the topographic subtypes of thalamic hemorrhage. Hematoma extension into the ventricles occurred in 70% of cases of the eldest group and in 52% of their younger counterparts, which is a significant difference. This finding suggests that the parenchymal degeneration observed with the aging process is an important factor that may contribute to the more catastrophic effect of ICH in the very elderly people [12, 13, 2124]. We have hypothesized that the aging process may imply changes in brain plasticity, a factor that may cause a decline in the strength of the brain tissue normally acting as a restriction wall to the extension of the hematoma [13]. The existing differences between the very elderly and the younger persons did not influence the immediate outcome, as evaluated by inhospital mortality rate, which contrasts with a previous report on all-cause ICH in persons aged 685 years [12]. However, given the small sample size of our study, it is possible that this nonsignificant difference (on a statistical basis) in mortality between the very elderly cohort and the control group is influenced by random bias and is thus a clinically significant difference (absolute difference in mortality of 12%). We observed that previous comorbidities and risk factors did not determine an immediate fatal outcome and that independent predictors of mortality were different from those resulting in differences between the 2 age groups. Also, further increasing in age in the very elderly group did not add any nega200
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tive effect on prognosis, which confirms previous findings on the importance of variables related to stroke severity and neurological deterioration as the main predictors of immediate unfavorable outcomes [13, 2528]. Apparently our results question whether a binomial age cutoff of 80 years is appropriate in distinguishing the patients with the highest probability of dying after ICH [29]. However, the present study is not powered to prove this issue. The reason of the lower blood pressure readings and the trend towards less obesity and diabetes mellitus in the very elderly people as compared with younger patients should be explored. Nonetheless, it supports the observation that persons reaching the very old age had fewer vascular risk factors earlier in midlife [17, 30] and thus reach an advanced old age with better quality of life. Usually this old-old population begins with chronic comorbidities late in life and spends !1 year of their lives in a medical institution [31]. The present report indeed has limitations, mainly the sample size and cross-sectional design that may be underpowered to detect some differences. Thus, the findings reported here should be interpreted cautiously. Further studies with a larger number of observations are necessary to confirm our results, especially longitudinal long-term analyses on prognosis. Of note is the fact that even when we studied a very old population, the frequency of lobar hemorrhages was only 12.5%, which emphasizes the participation of the established hypertension in the occurrence of ICH. However, it is important to underline that other causative or permissive factors were not definitively excluded. Cerebral amyloid angiopathy might play a role in the population described here, especially in the cases of lobar hematomas [22], for whom cerebral biopsy or necropsy was not performed. Therefore, taking into account the level of evidence provided here, hypertension should be considered as a precipitating factor of ICH, rather than a definite etiology.

Conclusions

Hypertensive very elderly patients presenting with ICH have several differences from their younger counterparts; however, these differences do not seem to impact significantly on the immediate outcome. Further research is needed to clarify whether very elderly patients with hypertensive ICH indeed have a distinct profile in risk factors and a different long-term prognosis influenced by biological variables other than age.

Chiquete et al.

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