Korean Journal of Cerebrovascular Surgery 2010;12(2):70-75.
Published online June 1, 2010.
Clinical Assessment of Risk Factors for the Intracerebral Hemorrhage in Patients with Chronic Renal Failure.
Byun, Hyoung Soo , Kim, Choong Hyun , Cheong, Jin Hwan , Kim, Jae Min
Department of Neurosurgery, Hanyang University Guri Hospital, Guri, Korea. kch5142@hanyang.ac.kr
Abstract
OBJECTIVE
Cerebrovascular and cardiovacular diseases are the main causes of death in patients with chronic renal failure (CRF) and who are undergoing hemodialysis. We investigated the risk factors for the development of intracerbral hemorrhage (ICH) in this population. METHODS: We retrospectively reviewed a total of 53 patients who underwent hemodialysis for CRF and who developed ICH. The patients' demographics, including gender and age, the duration of the hemodialysis, the initial Glasgow Coma Scale (GCS) score, the underlying causes of CRF, the past medication history, the location and amount of hemorrhage and the therapeutic modality for ICH were analyzed. RESULTS: The development of ICH significantly increased in the old age patients (> or = 65 years), the patients with a prolonged history of hemodialysis (> or = 5 years) and the patients with hypertension (p < 0.05). However, gender, anemia (hemoglobin < or = 8.0 g/dl) and the initial systolic blood pressure (> or = 180 mmHg) were not significantly correlated with the occurrence of intracerebral hemorrhage in the hemodialyzed patients. CONCLUSION: The present study suggests that the development of ICH in patients with CRF is increased in the old age patients, the patients with a prolonged history of hemodialysis and the medically co-morbid patients. To avoid this disastrous complication, we should try to minimize the modifiable risk factors of hemorrhagic stroke in CRF patients.
Key Words: Chronic renal failure, Hemodialysis, Intracerebral hemorrhage, Risk factors
 

Introduction


Heart failure and stroke are the leading causes of death in chronic hemodialyzed patients.22) Moreover, the occasional severe atherosclerotic changes in these patients make renal transplantation impossible. The previous reports on this may support the notion of an acceleration of atherosclerosis in hemodialyzed patients, yet many hemodialyzed patients with cardiovascular disease already have identifiable heart disease prior to starting hemodialysis.5) Additionally, there is a selected population of hemodialyzed patients who have multiple risk factors that have been established for the general population such as hypertension, hyperlipidemia, glucose intolerance, hyperuricemia and cigarette smoking.9)12) Therefore, it is still debatable whether chronic hemodialysis therapy may accelerate atherosclerosis.

Hemodialysis remains the standard therapy for chronic renal failure in Korea, as organ transplantation in Korea lags far behind other countries. The number of patients requiring chronic hemodialysis is increasing by 5~8% each year, and the recent advances have increased the proportion of patients receiving dialysis for over 10 years and dramatically prolonged the survival of patients with chronic renal failure (CRF).23) The incidence of cerebrovascular disease associated with chronic hemodialysis is reported to be 13.2~17.2 per 1000 patients per year.2)8)11) The incidence of intracerebral hemorrhage (ICH) is especially high, compared to cerebral infarction or subarachnoid hemorrhage, at 0.6-1.0% per year, which corresponds to a 5~10 times higher risk than that for the general population.8)9)12) In addition, the mortality rate of patients with chronic hemodialysis and who suffered from ICH is two times higher than that of non-hemodialyzed patients, and it was as high as 78.9% within 30 days from symptom onset.10)

Although there are many subclinical cerebrovascular diseases among patients with CRF, the evidence for the risk factors for stroke remains inconclusive. So, we analyzed the risk factors for ICH in hemodialyzed patients who have CRF.


Materials and Methods


Patients

Twenty-five patients who presented with ICH along with CRF and who underwent hemodialysis (Group A) at our department between January 1, 2005 and June 30, 2009 were eligible for this retrospective study. Control group (group B) included 28 patients who presented with CRF and who underwent hemodialysis, but they had no accompanying ICH in our hospital.

Inclusion into the study was consecutive and there was no systematic exclusion of patients. Informed consent was obtained from each patient. The patients?medical records were reviewed to document the demographic data, including gender and age, the initial high systolic blood pressure (≥180 mmHg), the underlying diseases, the hemoglobin concentration, the initial Glasgow coma scale (GCS) score, the cause of CRF, the duration of hemodialysis, the past medication history, the location and amount of ICH and the therapeutic modalities.

The diagnosis of ICH was based on the brain computed tomography (CT) finding on admission. Brain CT scans were obtained as soon as possible after hemodynamic stabilization. The volume (ml) of the hematoma was determined as A x B x C/2, which A, B and C were the maximum antero-posterior and medio-lateral diameters and height, respectively. The location of the ICH was also investigated and categorized as the ganglio-thalamic, cerebellar and subcortical regions and the brainstem.


Treatment

Stereotactic aspiration of the hematoma was performed in the patients who had 25~40 ml of ICH in the basal ganglia, thalamus or subcortical region. Craniotomy and hematoma removal were performed if the brain CT scans revealed a large hematoma (≥40 ml) and the patient had a low GCS score (less than 10). The patients with lobar hemorrhage and who had more than 100 ml of ICH, an age over 80 years old and a GCS score less than 4 were not operated on and they received palliative treatment. External ventricular drainage (EVD) was performed if hydrocephalus and/or intraventricular hemorrhage was also present.


Statistical analysis

The data was analyzed using SPSS software (version 11; SPSS Inc., Chicago, IL, USA). Student? t-test was used to identify the significant parameters. The Kruscal-Wallis test was employed to compare the differences of variables in 3 or more groups. Univariate analysis was performed and the odds ratio was obtained to identify the risk factors for the development of ICH in the CRF patients. Multiple logistic regression analysis for the significant factors on univariate analysis was done to identify the significant risk factors. Differences with a p value of 0.05 or less were regarded as statistically significant.


Results


Patient characteristics

The mean age of all patients was 59.9 years (range: 42 to 77 years) and 57% were males (n = 30) (Table 1). The mean duration of hemodialysis for CRF in group A was 7.33 years and the number of patients who underwent hemodialysis for more than 5 years was significantly higher than that in group B (Fig. 1). The initial systolic blood pressure in group A was higher than that in group B, yet the difference of the hemoglobin level was not significant. The initial GCS score in group A was 8 or less in 12 patients, 9 to 12 in 7 patients and 13 to 15 in 6 patients. The common causes of CRF in group A were hypertension and diabetes mellitus. In group B, there were 14 patients with diabetes mellitus. It was the most common cause of CRF, followed by hypertension in 9 patients, chronic glomerulonephritis in 3 patients and polycystic kidney disease in 2 patients. There was a significant difference in mean age, gender, the duration of hemodialysis, the initial systolic blood pressure and the initial GCS scores between group A and group B. The primary causes, including hypertension or diabetes mellitus, were also significantly different between group A and group B (Table 1). On the other hands, the mean volume of ICH was 45.76 ml (Fig. 2). All patients who developed ICH with CRF received hemodialysis before the onset of intracerebral hemorrhage, and also anticoagulant treatment with heparin. Some patients had also received oral aspirin or wafarin (10 patients) before symptom onset. None of the patients had a malignant tumor, hepatic cirrhosis or other systemic coagulopathies.

Location and treatment of ICH

The ICH was located in the ganglio-thalamic region in 11 patients, the subcortical region in 8 patients, the cerebellum in 4 patients and the brain stem in 2 patients. Surgical treatment for ICH was done in 18 out of 25 patients. The surgical patients were managed by craniotomy and removal of ICH in 8 patients, by a stereotactic procedure in 4 patients and the remaining 7 patients were treated by EVD only (Table 2).


Risk factors for the development of ICH in the CRF patients

Various factors for the development of ICH in CRF patients who were undergoing hemodialysis were identified. Univariate analyses showed that development of ICH was correlated with factor such as old age (≥ 65 years), a prolonged history of hemodialysis (≥ 5 years), a high initial systolic blood pressure (>180 mmHg) and hypertension or diabetes mellitus (Table 3). However, the regression analysis showed that the statistically significant factors included old age (≥ 65 years), a prolonged history of hemodialysis (≥ 5 years) and hypertension (Table 4).


Discussion


Patients with CRF frequently have advanced vascular disease compared to the general population.2)3)4)6)11)13)14)15)19)20)21) In particular, several authors have reported more severe atherosclerotic disease in the carotid arteries of CRF patients than that in the subjects with normal renal function.11)13)19)20)24) This accelerated disease of the cerebral vasculature could increase the risk of ischemic stroke in these patients. Additionally, CRF is commonly associated with hypertension, bleeding diathesis and administration of heparin during hemodialysis, which could increase the risk of hemorrhagic stroke. However, the evidence for an excess risk of stroke has not been defined with certainly. The only study that has estimated the rate of stroke in hemodialyzed patients and compared to that of the general population was performed in Japan.7)8)12) This study showed that the risk of hemorrhagic stroke in the hemodialyzed patients was higher than that in the general population, whereas the rates of ischemic stroke were equal to or lower than that of the general population. Furthermore, the hemodialyzed population in Japan tends to be younger and have fewer comorbid diseases than the hemodialyzed population in Korea.

There are a number of possible explanations for the excess risk of stroke among dialysis patients. Studies by Muntner, et al17) and Longnecker, et al16) have demonstrated that the traditional risk factors of stoke, such as diabetes, hypertension, cardiac disease and prior stroke, are much more common among the dialysis population than in the general population. However, it seems unlikely that the enormously higher risk of stroke observed in the CRF population can be explained purely by the differences in the prevalence of risk factors for stroke. An additional factor responsible for the higher stroke rates may be accelerated atherosclerotic vascular disease caused by uremia itself. This is supported by the reports that used noninvasive imaging techniques and these reports demonstrated a greater degree of carotid artery atherosclerosis among hemodialyzed patients compared to that of the controls subjects, and even after adjusting for the traditional cardiovascular risk factors.13)19)24) In addition to this accelerated vascular disease, other hemodialysis-specific factors could increase the risk of stroke for CRF patients. The sudden decreases in systemic blood pressure caused by hemodialysis could cause a reduction in cerebral perfusion, leading to ischemic stroke. Finally, the routine use of anticoagulation during hemodialysis could lead to an increased risk of hemorrhagic stroke. Chronic hemodialysis is also associated with impaired endothelium-dependent vasodilatation, which may reflect an increased susceptibility for the development of atherosclerosis and thrombosis.4) Iseki, et al7) have reported that incidence of cerebral hematoma was higher in old age patients and chronic hemodialysis patients. This finding is coincident with to our study. In an exploratory analysis, profound anemia (hemoglobin ≤ 8.0 g/dl) was associated with a significantly increased risk of stroke as compared with that for a hemoglobin level of 10 to 12 g/dl.12)  However, the level of hemoglobin in our study did not have an influence on the development of ICH.

The surgical indications for the evacuation of ICH remain to be controversial and especially for hemodialyzed patients. In our series, most patients had craniotomy and removal of hematoma because of the impending increased ICP. Stereotatic aspiration of hematoma and EVD were also performed in 4 patients. But the platelet dysfunction due to uremia and the coagulopathy due to anticoagulant therapy can result in difficulties to maintain hemostasis and there is an increased risk of rebleeding after surgery. So, for the management of ICH that develops during hemodialysis, conservative treatment has been recommended for the small sized and non-fatal ICH. Stereotactic aspiration is also an effective therapeutic modality for hematomas of moderate size. Craniotomy is generally performed only as critical care, but postoperative hemodialysis is likely to result in further hemorrhage.18)

The overall mortality for patients with ICH is very poor and it has been reported to be 53~73%  in the hemodialyzed patients.7)12)19) The major disadvantages of hemodialysis are hemorrhagic complications and dialysis disequilibrium syndrome. However, the use of anticoagulants with a short half-life, such as nafamostat mesilate or gabexate mesilate, and the concomitant use of osmotic diuretics during dialysis can reduce these risks. Therefore, hemodialysis may be considered to be a relatively safe procedure and even during the acute phase of cerebrovascular disease. Nafamostat mesilate, which has a minimal effect on systemic coagulation, has been reported to reduce the risk of increased bleeding caused by hemodialysis to 7.6% in patients with a tendency to bleed.1) The initial systolic blood pressure is one of the risk factors for ICH, but it may be affected by increased intracranial pressure. So, we thought that the initial systolic blood pressure could not be a risk factor of ICH.


Conclusion


This study suggests that the development of ICH in patients with CRF is increased in the old age patients, the patients with a prolonged history of hemodialysis and the patients with hypertension or DM. In the future, we need to analyze a larger patient population to obtain additional information on the risk factors for ICH in patients with CRF.


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