Age-Associated Vasospasm in Aneurysmal Subarachnoid Hemorrhage

Transcription

1 Age-Associated Vasospasm in Aneurysmal Subarachnoid Hemorrhage Sushant P. Kale, MD, MPH,* Randall C. Edgell, MD,* Amer Alshekhlee, MD,* Afshin Borhani Haghighi, MD,* Justin Sweeny, MD, Jason Felton, MD, Jacob Kitchener, MD,* Nirav Vora, MD,* Bruce K. Bieneman, MD,x Salvador Cruz-Flores, MD, MPH,* and Saleem Abdulrauf, MD The relationship between age and vasospasm caused by subarachnoid hemorrhage (SAH) is controversial. We evaluated this relationship in a contemporary sample from a single institution. In a retrospective study design, we included patients with SAH caused by ruptured intracranial aneurysms. All patients underwent an evaluation that included head imaging, cerebral angiography, and treatment for the underlying aneurysm. Vasospasm was classified as absent, any vasospasm, or symptomatic vasospasm. Age was classified into 2 categories with a cutoff of 50 years, and also was stratified by decade. All patients had received preventative and therapeutic measures for vasospasm. Logistic regression analysis was used to assess the association between age and the occurrence of vasospasm. A total of 108 patients were included in this analysis, 67 of whom were age $50 years. The older patients had a higher incidence of vascular risk factors, and the younger patients had a higher incidence of smoking and illicit substance abuse. The mean age of the patients with any vasospasm (n 5 41) was years, compared with years in those without vasospasm (P,.0001). Adjusted analysis found a greater risk of vasospasm in the younger patients compared with the older patients (odds ratio, 5.83; 95% confidence interval, for any vasospasm; odds ratio, 2.66; 95% confidence interval, for symptomatic vasospasm). This risk of vasospasm decreased with advanced age (P,.0001). Our findings suggest that patients age,50 years are at 5-fold greater risk of any vasospasm compared with older patients, and that age-adjusted prevention protocols may need to be considered. Key Words: Cerebral angiography spasm prevention demographics. Ó 2013 by National Stroke Association From the *Departments of Neurology and Psychiatry; Neurosurgery, Saint Louis University, St Louis, Missouri, MO; Transgenic Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; and xdepartment of Radiology, Saint Louis University, St Louis, Missouri, MO. Received December 1, 2010; revision received April 28, 2011; accepted May 21, Address correspondence to Amer Alshekhlee, MD, Saint Louis University, Souers Stroke Institute, Department of Neurology and Psychiatry, 1438 S Grand Blvd, St Louis, MO aalshekh@slu.edu /$ - see front matter Ó 2013 by National Stroke Association doi: /j.jstrokecerebrovasdis Cerebral arterial vasospasm after subarachnoid hemorrhage (SAH) is one of the major determinants of outcome. 1,2 Arterial vasospasm has been associated with increased mortality and morbidity rates and can lead to delayed ischemic neurologic deficit in 17%-40% of patients with aneurysmal SAH. 3,4 The relationship between the incidence of vasospasm and age is controversial and has not been studied in the setting of modern neurocritical care and neuroendovascular techniques. The nature of this relationship becomes important when one considers the risk associated with these techniques, especially in the elderly population. Although no studies have focused specifically on the role of age in association with the 22 Journal of Stroke and Cerebrovascular Diseases, Vol. 22, No. 1 (January), 2013: pp 22-27

2 AGE AND VASOSPASM IN SUBARACHNOID HEMORRHAGE 23 incidence of vasospasm, older studies examining a variety of possible predictors reached varying conclusions about the importance of this factor. Several studies found a trend toward less vasospasm with advancing age. 5,6 However, a post hoc analysis of a randomized trial of nicardipine in SAH found no relationship between age and angiographic spasm and actually found an increased incidence of symptomatic vasospasm in the older population. 7 These previous studies did not include the use of spasm-preventing medications, such as hydroxy- 3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, magnesium sulfate, and albumin, which in current use or under study in many neurocritical care units. In addition, these studies included the very early stages of endovascular treatment of vasospasm. Finally, these studies are limited by restrictive selection criteria in some cases and by limited numbers in others. In the present study, we examined the association between age and the occurrence of vasospasm in a modern, unselected population of consecutive patients with SAH due to ruptured cerebral aneurysm. In addition, we evaluated age-associated outcomes, including the presence of vasospasm, stroke, and modified Rankin scale (mrs) at hospital discharge. Methods Study Population and Protocol In a retrospective internal review board approved single-center protocol, we collected information about patients admitted with SAH due to ruptured cerebral aneurysm to Saint Louis University Hospital between July 2007 and July In addition to a clinical history consistent with SAH, the inclusion criteria included confirmatory imaging studies, such as computed tomography scan or brain magnetic resonance imaging. The clinical and radiologic severity of SAH was based on the Hunt Hess grade and Fisher grade, respectively. Patients with SAH due to other causes, such as head trauma, vascular malformation, and brain tumors, were excluded from the study. All patients underwent diagnostic cerebral angiography to evaluate the anatomy of the aneurysm. Treatment for these aneurysms, such as coil embolization, surgical clipping, or medical therapy alone, was ascertained. All patients were monitored in the intensive care unit for at least 14 days. During the monitoring period, patients received prophylaxis and treatment for seizure and vasospasm. Our institutional protocol for vasospasm prophylaxis included intravenous fluid and magnesium infusion, 8 along with HMG-CoA reductase inhibition (with statins) 9 and nimodipine. 10 The clinical diagnosis of symptomatic vasospasm was based on the development of focal neurologic deficits or a sudden decline in mental state without an identifiable cause other than confirmed vasospasm. In addition, all patients underwent serial transcranial Doppler ultrasonography studies at baseline and during the monitoring period to measure mean arterial velocity. A mean arterial velocity exceeding 200 m/s or a rapid increase in velocity from baseline was considered to indicate radiographic vasospasm. If vasospasm was suspected clinically or based on the transcranial Doppler or computed tomography angiography data, then maximal medical therapy, including induced hypertension, was implemented. In addition, diagnostic cerebral angiography was performed to evaluate the severity and anatomy of the spastic arteries and to assess the feasibility of local therapy. Interventional therapies for vasospasm included intra-arterial vasodilators (ie, local infusion of a calcium channel blocker into the spastic vessel) and/or angioplasty for a focal spastic lesion. Independent and Outcome Variables Independent demographic variables included patient age, sex, and ethnicity (white, black, and other). Age was stratified into 2 groups, young (age,50 years) and old (age $50 years), as well as by decade of life. Vascular risk factors included diabetes, hypertension, dyslipidemia, coronary artery disease, smoking, family history of cerebral aneurysm or SAH, and illicit substance abuse. Outcome variables included the presence of vasospasm (any vasospasm or symptomatic vasospasm). Age also was assessed in association with mrs score at hospital discharge. The mrs score ranges from 0 to 6, with 0 indicating no symptoms and 6 indicating death. The score was dichotomized as a favorable outcome (score of 0-2) or unfavorable outcome (score of 3-6). 11 Statistical Analysis The Student t test and Wilcoxon rank-sum test were used to compare the mean and median of continuous variables. The c 2 or Fisher exact test was used to compare categories. The significance level was set a priori at P,.05. A stepwise logistic multiple regression model was fitted to determine the independent association of significant variables (P,.20 on bivariate analysis) with the outcome of any vasospasm. Another model was constructed using the same variables for patients with symptomatic vasospasm only. Model goodness of fit was assessed using the Hosmer Lemeshow test. The Cochran Armitage test was used to evaluate linear trends of discrete variables (age category stratified by decade in relation to vasospasm and mrs score). Results Cohort Demographics Our study cohort comprised 108 patients admitted with a diagnosis of SAH. Table 1 presents basic demographic data stratified by age. Forty-one patients were aged,50 years, with a mean age of years; 67 patients

3 24 Table 1. Demographic of the study cohort stratified by age S.P. KALE ET AL. Age,50 years (n 5 41) Age $50 years (n 5 67) P value Age, years, mean 6 SD ,.0001 Race, n (%).41 White 25 (60.98) 48 (71.64) Black 11 (26.83) 11 (16.42) Others 5 (12.20) 8 (11.94) Sex, n (%).09 Male 8 (19.51) 23 (34.33) Female 33 (80.49) 44 (65.67) Vascular risk factors, n (%) Diabetes 0 8 (11.94).02 Hypertension 13 (31.71) 38 (56.70).01 Coronary artery disease 0 4 (5.97).11 Dyslipidemia 0 6 (8.95).04 Substance abuse 7 (17.07) 4 (5.97).06 Smoking 23 (56.10) 16 (23.88).0007 Family history of 5 (12.20) 4 (5.97).25 aneurysm/sah Hunt Hess scale, n (%).76 Grade 1 1 (2.44) 2 (2.99) Grade 2 16 (39.02) 24 (35.82) Grade 3 15 (36.59) 19 (28.36) Grade 4 5 (12.20) 14 (20.90) Grade 5 4 (9.76) 8 (11.94) Fisher scale, n (%).10 Grade 1 2 (4.88) 1 (1.49) Grade 2 11 (26.83) 9 (13.43) Grade 3 13 (31.71) 18 (26.87) Grade 4 15 (36.59) 39 (58.21) Treatment, n (%).25 None 4 (9.76) 11 (16.42) Surgical clipping 14 (34.15) 14 (20.90) Endovascular coiling 23 (56.10) 42 (62.69) Vasospasm, n (%)*.0005 None 16 (39.2) 51 (76.11) Any vasospasm 25 (60.09) 16 (23.88) Symptomatic vasospasm 12 (29.27) 9 (13.43) mrs score, n (%)y.69 Favorable 15 (36.59) 22 (32.84) Unfavorable 26 (63.41) 45 (67.16) *Patients with symptomatic vasospasm are subset of those with any vasospasm; thus the number of these cells does not match the total number of patients in each age category. ythe mrs score was dichotomized as favorable if the scale was 0-2 and as unfavorable if the scale was 3-6. were aged $50 years, with a mean age of years. There was no significant difference in ethnicity or sex distribution in the 2 age categories (P..05); however, predictably, the older patients had a higher incidence of vascular risk factors (hypertension, diabetes mellitus, and dyslipidemia; P,.05), whereas the younger patients had higher prevalences of smoking (56.10% v 23.88%; P ) and illicit substance abuse (17.07% v 5.97%; P 5.06). The severity of SAH based on the clinical (Hunt Hess grade) and radiologic (Fisher grade) scales was not different between the 2 age categories. The majority of patients were in Hunt-Hess grades 2 and 3 in both age groups (P 5.76); whereas the majority of patients were in Fisher grades 3 and 4 (P 5.10). Similar proportions of patients had received the treatments for aneurysm (P 5.25). Compared with the old group category, the younger population had higher incidence of any vasospasm (60.09% v 23.88%) as well as symptomatic vasospasm (29.27% v 13.43%). mrs score at hospital discharge was essentially similar in the 2 age groups (P 5.69). Table 2 demonstrates the same cohort stratified by the presence of any vasospasm. Forty one (37.9%) patients had any vasospasm; 21 (51.2%) of those were symptomatic. Patients with any vasospasm were younger ( versus

4 AGE AND VASOSPASM IN SUBARACHNOID HEMORRHAGE 25 Table 2. Bivariate analysis stratified by the presence of clinical vasospasm No vasospasm (n 5 67) Any vasospasm (n 5 41) P value Age, years, mean 6 SD ,.0001 Age category, n (%).003 Young (,50 years) 39 (58.2) 35 (85.4) Old ($50 years) 28 (41.8) 6 (14.6) Race, n (%).46 White 43 (64.2) 30 (73.2) Black 14 (20.9) 8 (19.5) Others 10 (14.9) 3 (7.3) Sex, n (%).43 Male 21 (31.3) 10 (24.4) Female 46 (68.7) 31 (75.6) Vascular risk factors, n (%) Diabetes 7 (10.5) 1 (2.4).12 Hypertension 31 (46.3) 20 (48.8).79 Coronary artery disease 3 (4.5) 1 (2.44).58 Dyslipidemia 6 (8.96) 0.04 Substance abuse 8 (11.9) 3 (7.3).44 Smoking 22 (32.8) 17 (41.5).36 Family history of 4 (5.97) 5 (12.2).25 aneurysm/sah Hunt-Hess scale, n (%).15 Grade 1 2 (2.99) 1 (2.44) Grade 2 25 (37.31) 15 (36.59) Grade 3 17 (25.37) 17 (41.46) Grade 4 12 (17.91) 7 (17.07) Grade 5 11 (16.42) 1 (2.44) Fisher scale, n (%).60 Grade 1 1 (1.49) 2 (4.88) Grade 2 14 (20.90) 6 (14.63) Grade 3 20 (29.85) 11 (26.83) Grade 4 32 (47.76) 22 (53.66) MRS score, n (%)*.66 Favorable 24 (35.82) 13 (31.71) Unfavorable 43 (64.18) 28 (68.29) *The mrs score was dichotomized as favorable if the scale was 0 2 and unfavorable if the scale was ; P,.0001). Among those without evident vasospasm, 39/67 (58.2%) were younger than 50 and 28/67 (41.8%) were older than 50. Among the vasospasm group, 35/41 (85.4%) were age,50 years, and 6/41 (14.3%) were age $50 years. Other than age, none of the basic demographics (sex and ethnicity), or the vascular risk factors were significantly different between the groups (P..05). Six patients without vasospasm had dyslipidemia compared to none in the vasospasm group (P 5.04). The mrs score on hospital discharge was similar among those with and without vasospasm (P 5.66). Among those treated with surgical clipping, 12/28 (42.86%) had vasospasm, compared to 28/65 (43.08%) among those treated with coil embolization (P 5.98). Outcomes Age was the only predictor for any vasospasm on multivariate logistic regression analysis (odds ratio [OR], 5.83; 95% confidence interval [CI], ). Younger age also predicted symptomatic vasospasm (OR, 2.66; 95% CI, ) compared to the older population (Table 3). None of the basic demographic data or vascular risk factors was associated with vasospasm. Three patients in the younger age group had sustained stroke with residual deficit as a result of vasospasm, compared with none in the older age group. Further trend analysis of age categorized by decade of life (Table 4) found a clear decline in the risk of any vasospasm with advanced age (P,.0001). A similar decline in the risk of symptomatic vasospasm with advancing age was noted (P 5.04). Only 1 patient under age 30 had any vasospasm while hospitalized; however, all patients under age 40 (n 5 26) had evidence of clinical or radiologic vasospasm. The majority of patients in both age categories had an unfavorable outcome (67.2% in those aged,50 and 63.4% in those age $50). The overall distribution of mrs scores was similar in the 2 age groups (Fig 1), including mortality rates (19.5% in

5 26 S.P. KALE ET AL. Table 3. Multivariate logistic regression analysis for outcome of symptomatic vasospasm and asymptomatic vasospasm Odds ratio (95% confidence interval) P value Goodness of fit (P value)* Any vasospasm, young (reference, old) Symptomatic vasospasm, young (reference, old) 5.83 ( ), ( ) *The Hosmer-Lemeshow test was used for the goodness of fit of the model. the younger patients, 19.4% in the older patients). Unfavorable outcome stratified by decade of age suggest that greater disability is more likely to occur with advanced age, but with no clear trend (P 5.15). Discussion Our findings support the inverse relationship between patient age and the incidence of vasospasm. 5,6 Although previous studies have evaluated many variables affecting the incidence of vasospasm, this study is the first to specifically explore the hypothesis that the incidence of vasospasm in SAH decreases with advancing age. Indeed, we found a higher incidence of vasospasm (60.09%) in patients aged,50 years. Further age stratification by decade suggests that the highest incidence of vasospasm occurred in those age,50. Our sample included only 1 patient younger than 30 who experienced asymptomatic vasospasm. SAH in general and symptomatic vasospasm in particular are associated with an unfavorable prognosis. 7 Although the incidence of vasospasm decreased with advancing age in our cohort, stratification of age by decade suggests a nonsignificant trend in outcome as assessed by mrs score at hospital discharge. The pathophysiological explanation for the decreasing incidence of vasospasm with age is not well understood. It is plausible that the higher prevalence and longer duration of vascular risk factors in the older population may play a role. Although chronic hypertension is implicated in the pathogenesis of atherosclerosis and subsequent arterial stiffness, its association with vasospasm has not been determined. The cerebral vessels of elderly patients may be less responsive to oxygen-reactive species as well as to endothelin, the biology of which has been implicated in chronic hypertension. 12 Endothelin receptor antagonists may prevent the occurrence of vasospasm associated with SAH due to ruptured cerebral aneurysm, even though they fail to improve clinical outcomes. 13,14 Interestingly, smoking (more prevalent in those aged,50 years in our cohort) increases the production of endothelin and reduces the production and bioavailability of nitric oxide, factors associated with vasospasm in the younger population. 15 Despite this plausible biological evidence, our regression analysis failed to show any association between smoking or chronic hypertension with vasospasm in SAH. Finally, the abuse of illicit substances, especially cocaine, has been associated with an increased risk of SAH; those patients are at a 2.8-fold increase risk of vasospasm. 16 This effect was not seen in our cohort, perhaps due to the small number of patients abusing illegal substances. The use of preventative therapies, such as magnesium sulfate, HMG-CoA reductase inhibitors, and albumin, was a part of our institutional protocol, even though these agents are still considered investigational. In addition, the use of coil embolization and endovascular management of vasospasm has increased dramatically over the last decade. 17 The addition of these treatment modalities might provide a benefit for patients at high risk for vasospasm; however, Table 4. Trends for vasospasm and mrs score stratified by age Age, years (n 5 108) Any vasospasm, n (%) Symptomatic vasospasm, n (%) Unfavorable mrs score, n (%)* (n 5 1) 1 (100.0) (n 5 15) 10 (66.6) 5 (33.3) 9 (60.0) (n 5 25) 14 (56.0) 7 (28.0) 17 (68.0) (n 5 35) 11 (31.4) 6 (17.1) 22 (62.8) (n 5 14) 2 (14.2) 1 (7.1) 8 (57.1) (n 5 13) 3 (23.1) 2 (15.4) 10 (76.9).80 (n 5 5) (100.0) P value for trendy, *Unfavorable mrs score if the scale was 3-6, with 6 indicating death. ythe Cochran Armitage test was used for trend analysis.

6 AGE AND VASOSPASM IN SUBARACHNOID HEMORRHAGE 27 Figure 1. mrs scores by age group. The mrs scores range from 0 to 6, with 0 indicating no symptoms and 6 indicating death. The scale was dichotomized as a favorable outcome (a score of 0-2) or unfavorable outcome (a score of 3-6), with 6 being death. Percentages in bracket indicate the proportion of those with favorable outcome and those with unfavorable outcome in both age groups (P 5.69). in the elderly population, the risk benefit ratio must be considered carefully. The components of so-called triple-h therapy (hemodilution, hypertension, and hypervolemia) may be associated with neurolologic and medical complications, such as worsening cerebral edema and hemorrhagic infarction, pulmonary edema, dilutional hyponatremia, and myocardial infarction. 18,19 These therapies often entail the use of invasive monitoring, such as Swan-Ganz catheters and intracranial monitors, which are associated with their own complications. 20 Elderly patients with more comorbidities are especially vulnerable to these complications; thus, an age-modified spasm prevention protocol may need to be considered. The limitations of the present study include the small number of patients who developed clinical vasospasm; however, our sample is comparable to that in most previous studies. In addition, this study is retrospective, and selection bias could not be eliminated. Regardless, our findings confirm that cerebral vasospasm is a more common complication in young patients with SAH due to a ruptured cerebral aneurysm. Therefore, adjusted preventive protocols geared toward young individuals may help reduce the incidence of this complication, and perhaps improve cost-effectiveness. References 1. Kassell NF, Torner JC, Haley EC Jr, et al. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results. J Neurosurg 1990; 73: Kassell NF, Torner JC, Jane JA, et al. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 2: Surgical results. J Neurosurg 1990;73: Adams HP Jr, Kassell NF, Torner JC, et al. Predicting cerebral ischemia after aneurysmal subarachnoid hemorrhage: Influences of clinical condition, CT results, and antifibrinolytic therapy. A report of the Cooperative Aneurysm Study. Neurology 1987;37: Haley EC Jr, Kassell NF, Torner JC, et al. A randomized trial of two doses of nicardipine in aneurysmal subarachnoid hemorrhage: A report of the Cooperative Aneurysm Study. J Neurosurg 1994;80: Charpentier C, Audibert G, Guillemin F, et al. Multivariate analysis of predictors of cerebral vasospasm occurrence after aneurysmal subarachnoid hemorrhage. Stroke 1999;30: Rabb CH, Tang G, Chin LS, et al. A statistical analysis of factors related to symptomatic cerebral vasospasm. Acta Neurochir (Wien) 1994;127: Lanzino G, Kassell NF, Germanson TP, et al. Age and outcome after aneurysmal subarachnoid hemorrhage: Why do older patients fare worse? J Neurosurg 1996; 85: Zhao XD, Zhou YT, Zhang X, et al. A meta-analysis of treating subarachnoid hemorrhage with magnesium sulfate. J Clin Neurosci 2009;16: Vergouwen MD, de Haan RJ, Vermeulen M, et al. Effect of statin treatment on vasospasm, delayed cerebral ischemia, and functional outcome in patients with aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis update. Stroke 2010;41:e47-e Deshaies EM, Boulos AS, Drazin D, et al. Evidence-based pharmacotherapy for cerebral vasospasm. Neurol Res 2009;31: Molyneux A, Kerr R, Stratton I, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: A randomised trial. Lancet 2002;360: Kohan DE. Endothelin, hypertension and chronic kidney disease: New insights. Curr Opin Nephrol Hypertens 2010;19: Kramer A, Fletcher J. Do endothelin-receptor antagonists prevent delayed neurological deficits and poor outcomes after aneurysmal subarachnoid hemorrhage? A metaanalysis. Stroke 2009;40: Macdonald RL. Clazosentan: An endothelin receptor antagonist for treatment of vasospasm after subarachnoid hemorrhage. Expert Opin Investig Drugs 2008; 17: Rahman MM, Laher I. Structural and functional alteration of blood vessels caused by cigarette smoking: An overview of molecular mechanisms. Curr Vasc Pharmacol 2007;5: Howington JU, Kutz SC, Wilding GE, et al. Cocaine use as a predictor of outcome in aneurysmal subarachnoid hemorrhage. J Neurosurg 2003;99: Alshekhlee A, Mehta S, Edgell RC, et al. Hospital mortality and complications of electively clipped or coiled unruptured intracranial aneurysm. Stroke 2010; 41: Corsten L, Raja A, Guppy K, et al. Contemporary management of subarachnoid hemorrhage and vasospasm: The UIC experience. Surg Neurol 2001;56: Shimoda M, Oda S, Tsugane R, et al. Intracranial complications of hypervolemic therapy in patients with a delayed ischemic deficit attributed to vasospasm. J Neurosurg 1993;78: Rosenwasser RH, Jallo JI, Getch CC, et al. Complications of Swan-Ganz catheterization for hemodynamic monitoring in patients with subarachnoid hemorrhage. Neurosurgery 1995;37: