|Year : 2018 | Volume
| Issue : 2 | Page : 127-133
Inflammatory markers and cerebral vasospasm after aneurysmal subarachnoid hemorrhage
Sherif Al-Kholy1, Mahmoud M Kenawi2, Ahmed Battah2, Mohamed Al-Desouky2
1 Intensive Care Unit Department, Nasser Institute of Research and Treatment, Egypt
2 Critical Care Department, Cairo University, Cairo, Egypt
|Date of Submission||04-Mar-2017|
|Date of Acceptance||12-Sep-2017|
|Date of Web Publication||28-Jun-2018|
Mahmoud M Kenawi
47, Zahraa Al-Maadi, Cairo, 11728
Source of Support: None, Conflict of Interest: None
Background Aneurysmal subarachnoid hemorrhage (aSAH) is considered a major cause of morbidity and mortality. It accounts for about 85% of spontaneous SAH. Cerebral vasospasm is a devastating complication of aSAH.
Aim The aim of this study was to evaluate the probable etiological determinant, the outcome of aSAH, and the role of inflammatory markers in predicting cerebral vasospasm post-SAH.
Patients and methods A prospective cohort study was conducted on aSAH patients who attended the Emergency Unit, Outpatient Clinics of Neurosurgery Department, and the ICU in Nasser Institute of Research and Treatment during the period between July 2014 and September 2016. Inflammatory marker samples were collected on days 0, 1, 3, 7, and 9. Patients were divided into two groups: (i) group A, which included patients with cerebral vasospasm (n=35) and (ii) group B, which included patients without cerebral vasospasm (n=25).
Results A total of 60 patients were enrolled. The mean age was highly significant between both groups (51.31±10.46 years in group A vs. 43.12±8.77 years in group B, P=0.002). The overall mortality was 18 patients, all of which in group A (P<0.001). The univariate analysis showed that C-reactive protein, total leukocytic count, and interleukin-6 had a significant statistical difference between both groups throughout the follow-up period (P<0.05). The optimal cutoff points as cerebral vasospasm indicator in days 0, 1, 3, 7, 9 were (i) 2.7, 4.6, 6.35, 7.45, and 3.8 mg/l for C-reactive protein; (ii) 9.79×109/l, 13.45×109/l, 9.75×109/l, 11.09×109/l, and 12.65×109/l for total leukocytic count; and (iii) 3.15, 3.95, 3.75, 5.1, and 5 pg/ml for interleukin-6, respectively.
Conclusion A strong correlation exists between inflammation, cerebral vasospasm, and poor survival outcomes among patients presenting with aSAH. Inflammation and inflammatory markers are dependent risk factors for mortality after cerebral vasospasm.
Keywords: aneurysmal subarachnoid hemorrhage, cerebral vasospasm, inflammatory markers
|How to cite this article:|
Al-Kholy S, Kenawi MM, Battah A, Al-Desouky M. Inflammatory markers and cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Res Opin Anesth Intensive Care 2018;5:127-33
|How to cite this URL:|
Al-Kholy S, Kenawi MM, Battah A, Al-Desouky M. Inflammatory markers and cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Res Opin Anesth Intensive Care [serial online] 2018 [cited 2018 Oct 16];5:127-33. Available from: http://www.roaic.eg.net/text.asp?2018/5/2/127/235484
| Introduction|| |
Spontaneous subarachnoid hemorrhage (SAH) is a common and frequently devastating condition and accounts for ∼10% of total stroke incidence . SAH occurs most commonly as a result of the rupture of intracranial aneurysm lesions, which are present in ∼2–5% of normal population .
Aneurysmal subarachnoid hemorrhage (aSAH) is a cerebrovascular disease with considerable health economic burden. It has an estimated incidence of 5–20 per 100 000 populations and a 30-day case mortality rate of 25–50% .
Patients with SAH commonly complicate with cerebral vasospasm, which is considered a devastating condition. Recently, the inflammatory role in the development and progression of cerebral vasospasm has been proved. A burgeoning (although incomplete) body of evidence suggests that various constituents of the inflammatory response, including adhesion molecules cytokines, leukocytes, immunoglobulins, and complement, may be critical in the pathogenesis of cerebral vasospasm .
The aim of this work is to evaluate the probable etiological determinant, the outcome of aSAH, and the role of inflammatory markers in predicting cerebral vasospasm post-SAH.
| Patients and methods|| |
This study was carried out on 60 patients who suffered from spontaneous SAH and attended the Emergency Unit, Outpatient Clinics of Neuropsychiatry Department and ICU in Nasser Institute of Research and Treatment in the period between July 2014 and September 2016. Our studied populations were more than 18 years old, admitted within the first 24 h postictus with spontaneous SAH. We excluded patients with traumatic SAH and those who had recent acute myocardial infarction, recent surgery, or died before completing 10 days of management.
Full clinical evaluation on admission was done including a full history, if possible, full neurological examination including scoring using the Glasgow Coma Scale (GCS). All patients were subjected to routine laboratory investigations, in addition to selected inflammatory markers [i.e. C-reactive protein (CRP), total leukocytic count (TLC), interleukin-6 (IL-6)]. Inflammatory marker samples were collected on days 0, 1, 3, 7, and 9. All patients underwent computed tomography (CT) scan, multi-slice CT, and four-vessel angiography for the localization of aneurysm or arteriovenous malformation.
Patients with cerebral vasospasm were diagnosed both clinically and radiographically. Clinical suspicion includes decline in the level of consciousness, confusion, facial asymmetry, or lateralizing signs. Radiographically, cerebral vasospasm was confirmed using CT angiography through visualizing narrowing of the lumen of a previously normal vessel. The vasospasm severity was assessed by Hunt and Hess Scale, World Federation of Neurologic Surgeons Grading System, Fisher Scale, and GCS System.
All patients were followed-up during the period of hospital stay, both clinically and radiographically using CT scan to detect hydrocephalic changes. Upon discharge, the patients’ clinical outcome was evaluated using the GCS and the Modified Rankin Scale.
The study was approved by the Ethics Committee of the Critical Care Department, Cairo University. All patients or their families signed a written consent before enrollment in the study.
The collected data were organized, tabulated, and statistically analyzed using SPSS software statistical computer package version 16 (SPSS Inc., Chicago, Illinois, USA). For quantitative data, the range, mean, and SD were calculated. For qualitative data, a comparison between two groups and more was done using χ2-test. Significance was adopted at P-value less than 0.05 for the interpretation of results of tests of significance ,.
| Results|| |
Our study population includes 60 patients, who were divided into two groups: (i) group ‘A’, which included 35 patients with spontaneous SAH with vasospasm and (ii) group ‘B’, which included 25 patients with spontaneous SAH with no vasospasm.
Age and sex
Our patient population had a highly significant difference in mean age between both groups (51.31±10.46 years in group ‘A’ vs. 43.12±8.77 in group ‘B’, P=0.002). Male sex counts for 57.1% in group ‘A’ versus 56% in group ‘B’, with nonsignificant difference ([Table 1]).
Analysis of comorbidities showed nonsignificant difference between both groups regarding hypertension and history of ischemic heart disease. On the contrary, diabetes mellitus and dyslipidemia were significantly different in both groups ([Table 2]).
Neurological examination showed significant difference in conscious level disturbance using GCS and seizures between both groups, whereas both headache and neck rigidity were nonsignificant ([Table 3]).
Results of inflammatory marker analysis showed the following:
Comparing the mean value of CRP between both groups showed that it was significantly high in group ‘A’ ([Table 4] and [Figure 1]).
|Table 4 Analysis of C-reactive protein levels in both groups during the follow-up period|
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A study of the correlation between CRP levels and the development of vasospasm after SAH in group ‘A’ showed that the optimal cutoff point of CRP was estimated to be 2.7 mg/l on day 0, 4.6 mg/l on day 1, 6.35 mg/l on day 3, 7.45 mg/l on day 7, and 3.8 mg/l on day 9 ([Table 5] and [Figure 2]).
|Figure 2 Receiver operating characteristic (ROC) curve showing correlation of C-reactive protein (CRP) and vasospasm.|
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Total leukocytic count
When coming to TLC level, we found that there was a highly significant difference in TLC levels between both groups ([Table 6] and [Figure 3]).
|Table 6 Analysis of total leukocytic count levels in both groups during the follow-up period|
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Our results showed that the TLC level is highly correlated with the development of vasospasm after SAH in group ‘A’ patients. The optimal cutoff point of TLC was estimated to be 9.79×109/l on day 0, 13.45×109/l on day 1, 9.75×109/l on day 3, 11.09×109/l on day 7, and 12.65×109/l on day 9 ([Table 7] and [Figure 4]).
|Figure 4 Receiver operating characteristic (ROC) curve showing correlation of total leukocytic count (TLC) and vasospasm.|
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Analyzing the IL-6 levels, we found that IL-6 levels are significantly higher in group ‘A’ compared with group ‘B’ ([Table 8] and [Figure 5]).
|Table 8 Analysis of interleukin-6 levels in both groups during the follow-up period|
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Studying the correlation between IL-6 levels and the development of vasospasm after SAH in group ‘A’ showed that the optimal cutoff point of IL-6 was estimated to be 3.15 pg/ml on day 0, 3.95 pg/ml on day 1, 3.75 pg/ml on day 3, 5.1 pg/ml on day 7, and 5 pg/ml on day 9 ([Table 9] and [Figure 6]).
|Figure 6 Receiver operating characteristic (ROC) curve showing correlation of interleukin-6 (IL-6) and vasospasm.|
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In our study, 18 out of 35 patients in group ‘A’ died versus none in group ‘B’. This resulted in highly significant difference (P<0.001) ([Figure 7]).
| Discussion|| |
The clinical outcome following cerebral vasospasm post-SAH is highly variable and likely depends on several factors. Numerous clinical variables have been identified as potential predictors of clinical outcome .
Our study was performed on 60 patients who suffered from spontaneous SAH. All patients were followed-up for at least 10 days from the day of admission.
In our study, we found significant effect of patient’s age on outcome as the mean age of patients in group ‘A’ was 51.31±10.46 years versus 43.12±8.77 years in group ‘B’ (P=0.002). This was in concordance with Lanzino and Kassell  where advanced age is a recognized prognostic indicator of poor outcome after SAH. Another observational study by Degos et al.  supported our finding, where elderly age and admission hydrocephalus predicted poor outcome.
Regarding sex, our study showed nonsignificant effect of sex on outcome after spontaneous SAH (male sex counts for 57.1% in group ‘A’ vs. 56% in group ‘B’, P=0.930). A study by Turan et al.  concluded that female sex is considered a risk factor for SAH occurrence, and although incidence of occurrence and mortality are confirmed to be higher in women, they elucidated no clear differences in the functional outcome among SAH survivors.
The current study showed that hypertension has no role in developing vasospasm, whereas further studies showed significant effect of hypervolemia and hypertension on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation after SAH causing cerebral vasospasm .
In our study, ischemic heart disease as a comorbidity had no effect in developing cerebral vasospasm due to the limited number of ischemic patients (only two patients). On the contrary, a study by Knekt et al.  have found that atherosclerotic heart disease is a very important risk factor for SAH and the resultant vasospasm due to thickening and narrowing of blood vessels and liberating mediators causing inflammation and formation of aneurysm, which may be ruptured by high intracranial blood pressure.
Our study showed that diabetes mellitus had a significant role in developing vasospasm (P=0.037). These data agree with the data of Badjatia et al. , in which there is relationship between hyperglycemia and symptomatic vasospasm. Other studies showed a reduction of incidence of cerebral vasospasm with control of hyperglycemia ,.
Dyslipidemia was significantly related with vasospasm in our study (31.4% in group ‘A’ vs. 4% in group ‘B’, P=0.009). This agrees with the studies by Strong and Richards , Durrington et al. , and Miller and Miller . They proved that dyslipidemia and hypercholesterolemia may be evidenced by increased concentrations of Apo B and decreased concentrations of high-density lipoprotein cholesterol, both of which are considered important risk factors for atherosclerosis, development, and rupture of cerebral aneurysms.
In our study, we found a strong relationship between occurrence of inflammation with rising CRP level and development of vasospasm post-SAH. CRP started elevation from day 0 after spontaneous SAH reaching the peak level on day 9. Continuous rise of CRP in our study showed poor prognosis and high mortality rate. This comes in agreement with other studies which found that CRP is a sensitive inflammatory marker. It is strongly stimulated by IL-6 ,,,,. A similar effect was noted by Romero et al. . The occurrence of clinical vasospasm was significantly correlated with higher CRP levels and patients with hemodynamic changes in transcranial Doppler showed higher CRP levels . In addition, Fountas et al.  have found that elevated CRP levels in serum and cerebrospinal fluid (CSF) were associated with increased incidence of angiographic vasospasm.
TLC is a strong predictor of vasospasm after spontaneous SAH. This was evident in our study. TLC started elevation from day 0 after spontaneous SAH reaching peak level on day 9. Continuous rise of TLC was strongly correlated with high mortality rate. This finding agrees with Mazlam and Hodgson  who stated that leukocytes may act by direct effects on the vasculature or indirectly through the elaboration and propagation of the inflammatory response leading to vasospasm and cerebral ischemia.
Rising IL-6 levels, in group ‘A’ patients, was found to be a strong predictor of vasospasm in patients presenting with spontaneous SAH and was related to high mortality rate. This comes in agreement with the study done by McMahon et al. . The plasma level of IL-6 could be an independent biomarker in predicting clinical outcome of patients with ruptured intracranial aneurysm ,. More studies support the hypothesis that an overwhelming inflammatory host response in the subarachnoid space of patients with SAH plays a central part in the pathogenesis of vasospasms and subsequent cerebral ischemia . The increase of IL-6 concentration in CSF occurs in patients after SAH in the acute phase of vasospasm. This was proved in the study published by Hendryk et al. .
- Our study included a limited number of patients. The larger the number of patients, the more the improved validity.
- Patients in ICU might receive many drugs that may affect the level of inflammatory markers and so might affect the results.
- Highly sensitive CRP and TLC and IL-6 may be affected by the long storage time for plasma samples.
| Conclusion|| |
A strong correlation exists between inflammation, cerebral vasospasm, and poor survival outcomes among patients presenting with spontaneous SAH. Inflammation and inflammatory markers are the dependent risk factors for mortality after cerebral vasospasm.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Feigin VL, Rinkel GJ, Lawes CM, Algra A, Bennett DA, van Gijn J, Anderson CS. Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies. Stroke 2005; 36:2773–2780.
Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med 2006; 354:387–396.
De Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol NeurosurgPsychiatry 2007; 78:1365–1372.
Aihara Y, Kasuya H, Onda H, Hori T, Takeda J. Quantitative analysis of gene expressions related to inflammation in canine spastic artery after subarachnoid hemorrhage. Stroke 2001; 32:212–217.
Dawson B, Trapp RG. Basic and clinical biostatistics [chapters 7–9]. 3rd ed. Medical Publishing Division, Lange Medical Book/McGraw-Hill; 2001. pp. 161–218.
Petrie A, Sabin C. Medical statistics at a glance. 2nd ed. Blackwell Publishing; John Wiley & Sons, Jul 27, 2009.
Flint AC, Smith WS. Predicting long-term outcomes for ischemic stroke based on admission variables. Stroke Rounds 2004; 2:1–6.
Lanzino G, Kassell NF. Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part II. A cooperative study in North America. J Neurosurg 1999; 90:1018–1024.
Degos V, Gourraud PA, Tursis VT, Whelan R, Colonne C, Korinek AM et al.
Elderly age as a prognostic marker of 1-year poor outcome for subarachnoid hemorrhage patients through its interaction with admission hydrocephalus. Anesthesiology 2012; 117:1289–1299.
Turan N, Heider RA, Zaharieva D, Ahmad FU, Barrow DL, Pradilla G. Sex differences in the formation of intracranial aneurysms and incidence and outcome of subarachnoid hemorrhage: review of experimental and human studies. Transl Stroke Res 2016; 7:12–19.
Meunech E, Horn P, Thome C, Roth H, Philipps M, Hermann P et al.
Effects of hypervolemia and hypertension on cerebral blood flow, intracranial pressure and brain tissue oxygenation after subarachnoid hemorrhage. Crit Care Med 2007; 35:1844–1851.
Knekt P, Reunanen A, Aho K, Heliövaara M, Rissanen A, Aromaa A, Impivaara O. Risk factors for subarachnoid hemorrhage in a longitudinal population study. J Clin Epidemiol 1991; 44:933–939.
Badjatia N, Topcuoglu MA, Pryor JC, Rabinov JD, Ogilvy CS, Carter BS, Rordorf GA. Preliminary experience with intra-arterial nicardipine as a treatment for cerebral vasospasm. Am J Neuroradiol 2004; 25:819–826.
Kruyt ND, Biessels GJ, de Haan RJ, Vermeulen M, Rinkel GJ, Coert B, Roos YB. Hyperglycemia and clinical outcome in aneurysmal subarachnoid hemorrhage: a meta-analysis. Stroke 2009; 40:424–430.
Bilotta F, Giovannini F, Caramia R, Rosa G. Glycemia management in neurocritical care patients. A review. J Neurosurg Anesthesiol 2009; 21:2–9.
Strong JP, Richards ML. Cigarette smoking and atherosclerosis in autopsied men. Atherosclerosis 1996; 3:451–476.
Durrington PN, Ishola M, Hunt L, Arrol S, Bhatnagar D. Apolipoproteins (a), AI and B and parenteral history in men with early onset ischemic heart disease. Lancet 1998; 1:1070–1072.
Miller GJ, Miller NE. Plasma high density lipoprotein concentration and development of ischemic heart disease. Lancet 1995; 1:16–19.
Fountas KN, Tasiou A, Kapsalaki EZ, Paterakis KN, Grigorian AA, Lee GP, Robinson JS Jr. Serum and cerebrospinal fluid C-reactive protein levels as predictors of vasospasm in aneurysmal subarachnoid hemorrhage. Clinical article. Neurosurg Focus 2009; 26:22–31.
Vajkoczy P, Meyer B, Weidauer S, Raabe A, Thome C, Ringel F et al.
Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study. J Neurosurg 2005; 103:9–17.
Goddard AJ, Raju P, Gholkar A. Does the method of treatment of acutely ruptured intracranial aneurysms influence the incidence and duration of cerebral vasospasm and clinical outcome? J Neurol Neurosurg Psychiatry 2004; 75:868–872.
Lynch JR, Blessing R, White WD, Grocott HP, Newman MF, Laskowitz DT. Novel diagnostic test for acute stroke. Stroke 2004; 35:57–63.
Mazlam MZ, Hodgson HJ. Interrelations between interleukin-6, interleukin-1 beta, plasma C-reactive protein values, and in vitro C-reactive protein generation in patients with inflammatory bowel disease. Gut 1994; 35:77–83.
Romero FR, Bertolini EG, Figueiredo EG, Teixeira MJ. Serum C-reactive protein levels predict neurological outcome after aneurysmal subarachnoid hemorrhage. Arq Neuropsiquiatr 2012; 70:202–205.
McMahon CJ, Hopkins S, Vail A, King AT, Smith D, Illingworth KJ et al.
Inflammation as a predictor for delayed cerebral ischemia after aneurysmal subarachnoid haemorrhage. J Neurointerv Surg 2013; 5:512–517.
Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 2011; 10:626–636.
Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ. Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke 2007; 38:1404–1410.
Fassbender K, Hodapp B, Rossol S, Bertsch T, Schmeck J, Schütt S et al.
Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries. J Neurol Neurosurg Psychiatry 2001; 70:534–537.
Hendryk S, Jarzab B, Josko J. Increase of the IL-1 beta and IL-6 levels in CSF in patients with vasospasm following aneurismal SAH. Neuroendocrinol Lett 2004; 25:141–147.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]