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Risk factors responsible for the volume of hemorrhage in aneurysmal subarachnoid hemorrhage
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.185398
Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a medical emergency with a high mortality and morbidity. There is a marked association of the ensuing neurological functional deficits following aSAH with the volume of hemorrhage. The volume of intracranial hemorrhage in aSAH is usually quantified by the revised Fisher grades. Keywords: Aneurysmal subarachnoid hemorrhage; aSAH, hemorrhage; risk factor
Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening neurosurgical condition caused by blood flow into the subarachnoid space following an intracranial aneurysm rupture. The overall mortality of aSAH throughout the world varies from 32% to 67%.[1] Bonita et al., reported a high mortality rate caused by aSAH: 36% in the first 2 days, 43% in the first week, and 57% during a one year recovery period.[2] A separate report from India indicated the average case fatality rate to be approximately 50% and with a trend towards a gradual increase in mortality with passage of time.[3] Among patients who survive the attack of aSAH, approximately one-third develop functional incapacitation of daily activities that often lasts a lifetime.[4] Furthermore, even patients who are able to live independently continue to have a reduced quality of life due to the development of sequelae of aSAH including personality changes, cognitive dysfunction, and major depression.[5],[6],[7] In aSAH, the volume of hemorrhage is closely associated with the development of functional deficits after aSAH.[8],[9],[10] The Fisher grade, proposed in 1980, and the revised Fisher grade, developed in 2001 from the initially proposed Fisher grade, are two scales based on the volume of hemorrhage present on the initial computed tomography (CT) scan.[11],[12] The significance of a higher Fisher grade in predicting the development of clinical deficits has lately been investigated by a number of studies. Oliveira et al., conducted a study using the Fisher grade to assess the progression of neurological sequel following aSAH. They reported that a poor Fisher grade was able to predict the likelihood of development of severe vasospasm.[12] Another group studied the development of cerebral ischemia after aSAH and found that the Fisher grade was a reliable predictor of delayed cerebral ischemia.[11] As the volume of intracranial hemorrhage is associated with significant morbidity and mortality following aSAH, it is important to determine the risk factors that may be responsible for determining the volume of SAH. In this manuscript, we performed a retrospective study of the risk factors including demographic characteristics, significant medical history, preadmission blood pressures, and aneurysm architecture, and evaluated their association with the volume of hemorrhage in aSAH as well as with the modified Fisher grades. Our data suggests that the preadmission diastolic blood pressure (DBP), multiple aneurysms, and aneurysms in the anterior communicating artery (ACOA) are associated with a higher volume of intracranial hemorrhage.
Study subjects A total of 155 patients who had suffered from aSAH, and were admitted to our department between September 2013 and February 2015, were analyzed retrospectively. Diagnosis of aSAH was confirmed by review of the neuroimaging studies including the CT scan, magnetic resonance imaging (MRI), or angiographic scanning. All patients received interventional embolization therapy. The study was approved by the ethics committee of the First Hospital of Hebei Medical University and an informed consent was taken from all the patients. We examined the individual patient notes for the following parameters: (1) The predisposing risk factors such as gender, age, hypertension, smoking, and diabetes mellitus; (2) preadmission conditions including systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure; (3) characteristics of ruptured aneurysms such as architecture, size, site (e.g., internal carotid artery [ICA], anterior communicating artery [ACOA], middle cerebral artery [MCA], posterior cerebral artery [PCA], anterior cerebral artery [ACA], basilar artery [BA], posterior interior cerebellar artery [PICA], superior cerebellar artery [SCA], vertebral artery [VA]), number of aneurysms, maximum lumen size of the aneurysms, aneurysmal neck length, and ratio of maximum lumen size to neck length. Blood pressure was measured using a calibrated mercury manometer on the right upper arm after the patients had rested for a minimum of 5 minutes. Definitions and normal values Hypertension was defined as SBP ≥140 mmHg and/or DBP ≥90 mmHg, according to the European Society of Hypertension (ESH) 2013 guidelines. Diabetes mellitus was diagnosed as fasting plasma glucose (FPG) ≥7.0 mmol/L or the 2-hour postprandial glucose (PG) levels during a 75-gram oral glucose tolerance test (OGTT) ≥11.1 mmol/L, according to the American Diabetes Association 2013 guidelines. Revised Fisher grade determined the hemorrhage volume that was visible on a plain CT scan and included the following grades: Grade 0 (no subarachnoid hemorrhage [SAH] or intraventricular hemorrhage [IVH]), grade 1 (minimal or thin SAH, no IVH in either of the lateral ventricles), grade 2 (minimal or thin SAH, with IVH in both the lateral ventricles), grade 3 (dense SAH with complete filling of ≥1 cistern or fissure, no IVH in either of the lateral ventricles), and grade 4 (dense SAH, with IVH in both the lateral ventricles).[12] Statistics analysis Statistical analysis was performed using SAS 9.2 (SAS Institute, Cary, NC, USA). Row mean scores differ test was first used to categorize variables of the revised Fisher grade. Variance test was then applied for independent multisamples in normal distribution and Kruskal–Wallis test for multisamples in non-normal distribution. Factors were considered to have significant association with aSAH volume when the individual P value was <0.05 in a logistic regression model.
Characteristics of the study population In total, 155 aSAH patients were analyzed in our study. The characteristics of the study population are summarized in [Table 1]. The mean age of the patients was 58 years. The ratio of female to male patients was approximately 3:1. Hypertension was diagnosed in 67.7% of the patients; a history of diabetes mellitus was found in 7.74% patients; and a history of cigarette smoking was found in 22.6% patients. The analysis of aneurysmal characteristics revealed that the majority of the patients (97.4%) had saccular aneurysms, and very few had the branching or fusiform type of aneurysms. ICA was the site of the aneurysm in 48.4% of the patients; ACOA in 20.7%; MCA in 12.3%; PICA in 7.1%; BA in 5.8%; ACA in 3.2%; PCA in1.3%; and SCA and VA in 0.6% patients each, respectively. One single aneurysm was observed in 77.4% of the patients. The maximum aneurysmal lumen size was 5.67 ± 2.56 mm (mean ± standard deviation [SD]), ranging from 1.1 to 16.5 mm. The aneurysmal neck length was 3.3 ± 1.5 mm, with the minimum being 1.0 mm and the maximum, 9.6 mm. The ratio of maximum lumen size-to-neck length was 1.9 ± 1.0, with the minimal and maximal values being 0.5 and 8.0, respectively. The preadmission SBP was 151.8 ± 26.7 mmHg; DBP, 90.8 ± 14.6 mmHg; and pulse pressure, 61.0 ± 17.6 mmHg. Patients were classified according to the revised Fisher grade; 16.1%, of patients were categorized in Fisher grade 0; 11.0% in grade 1; 54.8% in grade 2; 14.8% in grade 3; and the remaining 3.2% in grade 4.
Univariable analysis of the risk factors responsible for the volume of hemorrhage In this study, we chose gender, age, hypertension, diabetes mellitus, smoking, preadmission SBP, DBP, pulse pressure, and aneurysm characteristics (site, size, number, maximum lumen size, neck length, and ratio of maximum lumen size to neck length) as independent variables [Table 2]. We used the stratified revised Fisher grades as dependent variables. We identified that the aneurysm number in a patient was significantly related to a poor Fisher grade (grade 3 or 4; P = 0.016). Significant difference was also observed in the site of aneurysms (ICA, ACOA, MCA, etc.; P < 0.001). Additionally, preadmission DBP alone was significantly associated with a poor Fisher grade (P = 0.024) compared with the preadmission SBP (P = 0.160) and pulse pressure (P = 0.438). With this method, we did not observe a statistically significant association between the Fisher grades and the risk factors in terms of gender, smoking, diabetes mellitus, hypertension, aneurysm architecture, age, maximal lumen size, neck length, and ratio of maximal lumen size to neck length.
Multivariable analysis of the risk factors responsible for the volume of hemorrhage Furthermore, we examined the impact of variable risk factors on hemorrhage volume by using multivariable analysis. Presented in [Table 3], we found that bleeding of the ACOA was significantly associated with a poor Fisher grade (odds ratio [OR] =4.3, P = 0.025). Of note, bleeding in the ICA was inversely associated with Fisher grades 0–2 in aSAH (OR = 0.6, P < 0.001). Additionally, we identified that the presence of multiple aneurysms (2–4) was a significant risk factor of a poor Fisher grade (OR = 4.0, P = 0.004). An MCA artery aneurysm, on the contrary, had no statistical significance in increasing the likelihood of a poor Fisher grade (OR = 4.1). Although a high preadmission DBP was significantly associated with a poor Fisher grade (P = 0.047), it was not a clinically relevant risk factor (OR = 1.0). Similar to the univariable analysis, Fisher grade had no correlation with the other variables.
aSAH, characterized by acute bleeding into the subarachnoid spaces, may occur due to a number of pathologic processes, including rupture of the cerebral aneurysm, head injury, cerebral arteriovenous malformation, moyamoya disease, and arteriovenous fistula. It is considered as a medical emergency given that it frequently leads to death or severe disability. Screening for aneurysms and if found, an early intervention in order to obliterate them, are, therefore, crucial in reducing the mortality and morbidity in high-risk patients, for example, in patients having two or more first-degree relatives who have had an aSAH. Furthermore, certain risk factors contribute to the aSAH hemorrhage volume, which is quantified by the Fisher grade and is directly associated with an increased mortality and occurrence of functional deficits following aSAH. In this study, we analyzed the relationship between demographic factors, medical history, aneurysm features, and Fisher grades as a measure of hemorrhage volume. Our data indicated that the incidence of aSAH was related to female gender, hypertension, and saccular-type aneurysms. Previous studies have also reported hypertension as a risk factor of aSAH.[13],[14] We specifically focused on the preadmission blood pressures, which were blood pressures that were recorded without any antihypertensive management after the onset of aSAH. Our hypothesis was that pre- and post-management blood pressures differ in the impact that they have on the volume of intracranial hemorrhage. Our results indeed revealed that the preadmission DBP was associated with poorer Fisher revised grades, and that a high DBP contributed to a greater hemorrhage volume. To our knowledge, the present study was the first to discover this finding in the Chinese population, and we suggest that aggressive management of the preadmission DBP may be beneficial in improving outcomes in aSAH patients. We reason that in the early stages of aneurysm rupture, appropriate blood pressure control could greatly reduce the risk of aneurysmal rerupture and rebleed. Conversely, at the end of acute management of aSAH, the blood pressure needs to be restored to avoid cerebral hypoperfusion and vasospasm. The site of aneurysm is one important aspect that influences the volume of aSAH.[15] MCA and ICA aneurysms have been suggested by a number of studies to be related to aSAH.[15],[16] However, there was a debate regarding the significance of ACOA aneurysms in influencing the volume of aSAH in the past decades. Daniella et al., conducted a study in the Canadian population and reported worse outcomes in patients with ACOA aneurysms in the last 45 seconds of the phonemic fluency test.[17] The study by Kerim et al., however, suggested that there was no influence of aneurysms of the anterior cerebral arteries including the ACOA in determining outcome of aSAH.[18] Although studies of a wider population are still needed, our study in the Chinese population has observed the ACOA to be a major risk factor of poor grade in aSAH. Our study suggests that ACOA aneurysms may influence the severity of hemorrhage and that early surgical intervention may be indicated in these patients. Multiple aneurysms accounted for approximately 25% in our study. We found that multiple aneurysms had a greater OR in contributing to unfavorable outcomes in patients with aSAH. We noted that the relative low statistical power in the univariable analysis (P = 0.016) could have resulted from the limited number of patients with multiple aneurysms in our study. In daily practice, we found that patients with multiple aneurysms were typically associated with larger bleeding volumes, possibly due to their higher blood pressures, or due to the presence of preexisting vascular malformations. Given that early surgeries in poor-grade patients may improve outcomes,[19] we recommend an early surgical intervention instead of conservative management in aSAH patients with multiple aneurysms if our findings could be confirmed in a larger study cohort or meta-analysis. Admittedly, there were a few limitations in our study. First, our case number was restricted. A larger number is needed to sanctify our conclusions. Second, the combined influence of multiple factors, such as hypertension and smoking, has recently been recognized for its involvement in aSAH.[20] Further work is needed to determine whether the interaction of these risk factors has influenced the current study. We also need to determine the prognostic value of individual risk factors in influencing the patients' overall survival. Nonetheless, our study represents the first effort to investigate the risk factors influencing the volume of aSAH. We identified that preadmission DBP, multiple aneurysms, and aneurysms of ACOA markedly increased the volume of hemorrhage. Patients harboring aneurysms with the aforementioned features are encouraged to seek an early intervention and prevent the occurrence of aSAH by an early treatment of these modifiable factors. Financial support and sponsorship Nil. Conflicts of interest All authors declare that they have no potential conflicts of interest.
[Table 1], [Table 2], [Table 3]
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