Cardiac Troponin Elevation and Outcome after Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis

Cardiac Troponin Elevation and Outcome after Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis Limin Zhang, MD, Zhilong Wang, MM, and Sihua Qi, PhD

Background: Cardiac abnormalities frequently occur after subarachnoid hemorrhage (SAH). Cardiac troponin (cTn) is a preferred biomarker for the diagnosis of cardiac damage, and the clinical significance of cTn elevation after SAH remains controversial. This meta-analysis was performed to assess the association between cTn elevation and patient outcomes, including delayed cerebral ischemia (DCI), poor outcome (death or dependency), and death in SAH patients. Methods: PubMed, Embase, and the Cochrane Library were searched for observational studies reporting an association between cTn elevation and outcome after SAH that were published before December 31, 2014. We extracted data regarding patient characteristics, cTn elevation, and outcome measurements (DCI, poor outcome, or death). Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Results: Twelve studies involving 2214 patients were included in data analysis. Elevation of cTn was observed in 30% of the patients. The cTn elevation was associated with an increased risk of DCI (RR, 1.48; 95% CI, 1.23-1.79), poor outcome (RR, 1.91; 95% CI, 1.51-2.40), and death (RR, 2.53; 95% CI, 2.04-3.12). At the 3- and 12month follow-ups, cTn elevation was associated with higher rates of DCI (RR, 1.51; 95% CI, 1.11-2.07), poor outcome (RR, 1.91; 95% CI, 1.51-2.40), and death (RR, 2.78; 95% CI, 1.80-4.29). At in-hospital follow-ups, cTn elevation was also associated with the higher rate of death (RR, 2.33; 95% CI, 1.76-3.07). Conclusions: cTn elevation in SAH patients is associated with an increased risk of DCI, poor outcome, and death after SAH. Key Words: Subarachnoid hemorrhage—cardiac troponin—cardiac abnormalities—delayed cerebral ischemia—poor outcome—death. Ó 2015 by National Stroke Association

Subarachnoid hemorrhage (SAH) is a common critical disease with approximately 50% fatality.1 In addition to the impact caused by the initial bleeding and subsequent neurologic damage, neurocardiogenic injury has been linked with increased morbidity and mortality in patients with SAH.2-4 Neurocardiogenic injury is believed to be a

From the Department of Anaesthesiology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China. Received April 3, 2015; revision received June 11, 2015; accepted June 24, 2015. Address correspondence to Sihua Qi, PhD, Department of Anaesthesiology, The Fourth Affiliated Hospital, Harbin Medical University, Yiyuan street 37, Harbin 150001, China. E-mail: sihuaqi2014@ 163.com. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.06.030

neurally mediated process as a consequence of brain damage rather than manifestation of coronary artery disease,5,6 which could further aggravate the changes in cerebral blood flow induced by SAH.6 Cardiac troponins (cTn) T and I provide largely identical information and are widely used as the preferred biomarkers for the diagnosis of myocardial infarction7 and cardiac damage after SAH.8-10 Cardiac abnormalities including cTn elevation were associated with poor outcome in patients with SAH in a previous meta-analysis.2 cTn is positively correlated with the severity of SAH (Hunt–Hess scale), arrhythmias like ventricular tachycardia/fibrillation, and regional wall motion abnormalities (WMAs).3,11 One study found, after adjusting for admission Hunt–Hess grade, age, and aneurysm size, that cTnI elevation was significantly associated with vasospasm and mortality.10 Indeed, an association between cTn elevation and poor outcome after

Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-10

1

L. ZHANG ET AL.

2 12-

SAH has been demonstrated based on previous studies. 18 Many studies with multiple sequential measurements have been recently published. Therefore, this metaanalysis was performed on observational studies to assess the association between cTn elevation and the occurrence of delayed cerebral ischemia (DCI), poor outcome, and death after SAH.

Materials and Methods We conducted this study according to the methods of the Cochrane Handbook for Systematic Reviews of Interventions. The findings are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Search Strategy Two librarians independently searched PubMed, Embase, and the Cochrane Library for studies describing the association between the cTn elevation and outcome after SAH that were published before December 31, 2014. The following key words were used: ‘‘subarachnoid haemorrhage’’ OR ‘‘subarachnoid hemorrhage’’ OR ‘‘subarachnoid blood’’ OR ‘‘subarachnoid bleeding’’ OR ‘‘intracranial bleeding’’ OR ‘‘intracranial aneurysm’’ OR ‘‘SAB’’ OR ‘‘SAH.’’ Each of these key words was combined with the key word ‘‘troponin.’’ The bibliographies of previous reviews and the included publications were also manually checked to identify other potentially relevant studies. This procedure was repeated until no further relevant studies were found.

Study Selection Two authors (L.M.Z. and Z.L.W.) independently assessed the eligibility of studies. Only studies published in English were included in this review. We included observational studies that examined the association between cTn and outcome after SAH. SAH was required to be documented by either computed tomography (CT) scanning or cerebrospinal fluid examination. cTnI assays are made by multiple manufacturers and different antibody pairs are used by each manufacturer, so cTn assays are different and not interchangeable in the included studies. The upper limits of normal cTn varied across the included studies and were based on the description in each article. Outcomes after SAH were defined as DCI, poor outcome, or death. Meeting abstracts, case reports, reviews, and studies with fewer than 10 patients were excluded. Only studies that included consecutive patients were eligible to avoid selection bias. In the case of duplicate or overlapping data, only the report with the largest number of patients was used for data extraction. Disagreements with respect to the literature search and study eligibility were resolved by discussing the article in question until a consensus was reached.

Quality Assessment and Data Extraction The 2 authors involved in selecting the studies also evaluated the quality of the included studies using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist (https://www. strobe-statement.org). For every article, the 2 authors (L.M.Z. and Z.L.W.) independently assigned a score (either 0 or 1) to each of the 22 STROBE items; these scores were then added to yield the STROBE score. Several STROBE items consist of subitems which were also scored as 0 or 1 and then averaged. The 2 authors solved disagreements by direct communication. We extracted the following data: definition of inclusion and exclusion criteria, the last name of the first author, publication year, study design (prospective cohort study or retrospective cohort study), number of included patients, sex, mean age, follow-up period, patients with poor condition on admission and patients with DCI, poor outcome, or death. In cases of disagreement, the investigators reviewed the article in question together until a consensus was reached. Neurologic condition on admission was dichotomized as either ‘‘poor’’ or ‘‘good’’ based on the following scoring system used in the particular article: Hunt–Hess,19 World Federation of Neurosurgical Societies,20 Glasgow Coma Scale,21 or Botterell.22 Poor condition on admission was defined as a Hunt– Hess score of 3 or more, WFNS score of 3 or more, GCS score of less than 12, or a Botterell score of 3 or more. As a determinant, we extracted the incidence of cTn elevation on admission. If the studies included other determinants, we also extracted these for summary purposes, including echocardiographic WMAs, abnormal admission electrocardiograph (T-wave inversion, ST-segment abnormalities, Q waves, or QTc prolongation), elevated brain natriuretic peptide (BNP), and elevated N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). The number of patients with DCI, the number of patients with poor outcome, and the number of deaths from any cause were recorded as outcome measurements. Poor outcome was defined as death or dependence on daily living activities, based on a handicap scale such as the modified Rankin Scale (dichotomized at . 3) or the Glasgow Outcome Scale (dichotomized at # 3). There were several definitions of DCI among the various studies. Considering the heterogeneity of DCI definitions, we simply extracted the number of patients with DCI reported by the studies without adjusting these numbers using a predefined DCI definition. Data regarding therapy were not assessed here, as such information was not present in several of the included studies.

Data Synthesis Relationships between the 3 outcome measurements and cTn elevation were analyzed. The crude proportions

CARDIAC TROPONIN ELEVATION AND OUTCOME AFTER SAH

of the extracted variables were calculated. Cross-tables were constructed to calculate risk ratios (RRs) for outcome and each determinant in each study. We calculated the pooled RRs with their corresponding 95% confidence intervals (CIs) using a random-effects model with Cochrane’s Review Manager version 5.3 (The Cochrane Collaboration, London, United Kingdom). We also tested the statistical heterogeneity (I2) of the effects using the same program; a value greater than 50% was considered to indicate significant heterogeneity.23

Results Study Characteristics The initial search retrieved 399 studies that reported troponin after SAH, and no additional studies were found through other sources (Fig 1). After title screening and detailed abstract evaluation, 46 studies were selected. After detailed evaluation of the full 46 article, 12 studies8-12,18,24-29 were selected for inclusion in this review. No overlap was found among these 12 studies. No study was excluded based only on language.

Figure 1. Flow diagram of the employed search strategy and study selection.

3

Baseline Characteristics Table 1 shows the baseline characteristics of patients included in the meta-analysis. Twelve studies involving a total of 2214 patients were included. The follow-up duration (for outcome assessment) varied from followup during the hospital stay (a few days or discharge, 6 studies) up to 12 months of follow-up. The percentage of patients with DCI varied from 6% to 54% (mean, 27%; 5 studies). The definitions of DCI were varied and included scores of temporary focal neurologic signs,8 neurological deterioration and imaging evidence of spasms or CT evidence of infarction,9 neurological deterioration with imaging evidence of spasms,10 neurological deterioration excluding other causes (using CT),12 or probable and definite DCI as one event.24 Table 2 presents the proportions of patients with cardiac abnormalities. The cTn elevation was reported in 21% to 52% of patients (mean, 30%; 12 studies). The values of cTn were measured during the period of acute stage of SAH. It was measured repeatedly for consecutive days,8-12,27 on the day of admission only,18,24,26,28 or both.25,29

L. ZHANG ET AL.

4

Abbreviations: DCI, delayed cerebral ischemia; P, prospective cohort study; R, retrospective cohort study; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology. *Poor outcome was defined as a modified Rankin scale score of .3, otherwise as a Glasgow Outcome Scale score of #3. yA poor condition on admission was considered when WFNS was .3, otherwise when Hunt–Hess was $3. zBaseline characteristics in the provided study were for 239 patients, although only 203 patients were analyzed for poor outcome.

5 (13) 7 (16) 70 (28) — 38 (13) 31 (37) 16 (17) — — 64 (17) 51 (23) 58 (19) 340/1703 (20) — — 117 (46) * 40 (59)* — — — 36 (24) 59/203 (29)z — — 66 (22)* 318/1029 (31) 16 (41) 19 (44) 33 (13) — 18 (6) — — — — — — 164 (54) 250/936 (27) In hospital In hospital 3 mo 3 mo In hospital In hospital In hospital 3 mo 3 mo 12 mo In hospital 3 mo 14 (36) 25 (58) 171 (68) 32 (47)y 147 (49) — — 121 (59) 139 (58) — 122 (56) 145 (48) 916/1672 (55) P P P P P R P P P P R P 10/12 54 55 55 — 55 59 51 55 54 50 57 57 54 39 43 253 68 300 83 91 204 239 368 225 301 2214 Parekh, 20008 Deibert, 20039 Naidech, 200510 Schuiling, 200518 Yarlagadda, 200612 Ramappa, 200825 Sandhu, 200826 Hravnak, 200911 Miketic, 201027 Degos, 201228 Gupte, 201329 Bilt, 201324

61 67 72 78 69 60 66 71 72 64 67 70 69

18 14 17 17 18 18 17 19 14 18 18 20 Median 18

Follow-up period Poor condition on admission, n (%) Study design STROBE score Mean age Female (%) No. of patients Author/year

Table 1. Baseline characteristics of the included studies

DCI, n (%)

Poor outcome, n (%)

Deaths, n (%)

Relation of Determinants with Outcome The chosen end points are not represented in every included study, and therefore, only a fraction of the studies were included in the specific analyses (DCI, poor outcome, or death). Figure 2 shows the pooled RRs and corresponding 95% CIs of cTn elevation for DCI, poor outcome, and death. cTn elevation showed significant associations with higher rates of DCI (RR 5 1.48; 95% CI; 1.23-1.79; P , .0001; I2 5 0%), poor outcome (RR 5 1.91; 95% CI, 1.51-2.40; P , .00001; I2 5 0%), and death (RR 5 2.53; 95% CI, 2.04-3.12; P , .00001; I2 5 0%). Figure 3 shows the pooled RRs and corresponding 95% CIs of cTn elevation for DCI, poor outcome, and death at 3- and 12-month follow-ups after hospital discharge. cTn elevation showed significant associations with higher rates of DCI (RR 5 1.51; 95% CI, 1.11-2.07; P 5 .010; I2 5 57%), poor outcome (RR 5 1.91; 95% CI, 1.51-2.40; P , .00001; I2 5 0%), and death (RR 5 2.78; 95% CI, 1.80-4.29; P , .00001; I2 5 42%). Figure 4 shows the pooled RRs and corresponding 95% CIs of cTn elevation for DCI and death at in-hospital follow-ups. cTn elevation was not associated with higher rates of DCI (RR 5 1.44; 95% CI, .87-2.38; P 5.15; I2 5 0%). By contrast, cTn elevation showed significant association with higher rates of death (RR 5 2.33; 95% CI, 1.76-3.07; P , .00001; I2 5 0%). Figure 5 shows the pooled RR and corresponding 95% CI of cTn elevation for SAH severity by poor condition on admission. Additionally, the heterogeneity of the data (I2) is presented. In particular, a significantly higher number of patients with cTn elevation exhibited greater SAH severity (RR 5 1.60; 95% CI, 1.35-1.91; P , .00001; I2 5 24%). Figure 6 shows the pooled RRs and corresponding 95% CIs of SAH severity for DCI, poor outcome, and death. SAH severity was significantly associated with higher rates of DCI (RR 5 1.61; 95% CI, 1.26-2.05; P 5 .0001; heterogeneity, not applicable), poor outcome (RR 5 2.81; 95% CI, 1.99-3.98; P , .00001; I2 5 4%), and death (RR 5 4.26; 95% CI, 2.67-6.82; P , .00001; I2 5 0%).

Discussion Although the primary causes of poor outcome and death after SAH are the initial hemorrhage and neurologic complications, this systematic review and metaanalysis indicates that the cTn elevation after SAH is associated with higher rates of DCI, poor outcome, and death. Circulating cTn elevation after SAH differs from that after ischemic heart disease with respect to pathophysiological mechanism.2 Earlier studies, based on limited evidence, attributed cardiac dysfunction after SAH to oxygen supply–demand mismatch in the settings of

CARDIAC TROPONIN ELEVATION AND OUTCOME AFTER SAH

5

Table 2. Prevalence of cardiac abnormalities [cTn Reference 8 9 10 18 12 25 26 11 27 28 29 24

Total

Period

N (%)

WMA

Abnormal admission ECG

[BNP

[NT-proBNP

7d $3 d 8d 24 h 5d — 24 h 5d 5d On admission — On admission

8 (21) 12 (28) 126 (50) 35 (52) 52 (22) 31 (37) 20 (21) 64 (31) 80 (33) 80 (22) 47 (23) 97/261 (37)z 652/2174 (30)

5 (13) 7 (16) 55 (22) — 45 (19) — — 19 (15) — — 15 (9) 59/301 (20) 205/1365 (15)

— — 174 (69)* — — 71 (92)y — 82(40) — — — 145/301 (48) 472/841 (56)

— — — — 14 (9) — — — — — — — 14/150 (9)

— — — — — — — — — — — 159 (71) 159/225 (71)

Abbreviations: cTn, cardiac troponin; BNP, brain natriuretic peptide; ECG, electrocardiograph; NT-proBNP, N-terminal prohormone of Btype natriuretic peptide; WMA, echocardiographic wall motion abnormality. Data are presented as a number (percentage). *Q wave, QTc prolongation (..4 ms), T-wave inversion, or ST-T–segment abnormality. yQTc prolongation and ST depress; others are QTc prolongation. zElevated troponin T; otherwise elevated troponin I.

hypertension and tachycardia, epicardial coronary vasospasm, and coronary thrombosis.13,30 In addition, several studies showed that some SAH patients display echocardiographic and electrocardiographic anomalies that are suggestive of myocardial ischemia without angiographic evidence of coronary artery vasospasm or disease.5,31 However, myocardial ischemia is an unlikely cause of this dysfunction, as myocardial perfusion was reportedly normal4 and transient regional WMAs in SAH patients typically extend beyond the territory of a single coronary artery.5,8,24,32,33 A more generally accepted hypothesis is that sympathetic stimulation induces catecholamine release in the myocardium, which may lead to impaired systolic and diastolic function, repolarization abnormalities, and myocardial damage.2-4,34,35 Troponin is a highly specific and sensitive marker of cardiac injury.7 The troponin complex is composed of 3 protein subunits, troponins T, I, and C. Troponins T and I exhibit unique cardiac isoforms, whereas cardiac and skeletal muscles share troponin C isoforms, rendering this protein unsuitable for diagnostic use. cTn are complexed with actin in cardiac myofibrils, with a small fraction (3%-6%) soluble in the cytoplasm.36 cTn T and I are widely used as biomarkers for myocardial necrosis in patients with suspected acute coronary syndrome.37 Troponin is included in a 6-parameter panel—including 4 brain injury–related proteins, 1 cardiac marker, and a clinical score—used to predict 6-month outcome.38 The present study demonstrates an association between cTn elevation and poor outcome after SAH.

However, whether there is a causal relationship between these variables remains unclear. Several studies have found an independent effect for cardiac abnormalities on outcome after adjusting for clinical variables (eg, age, gender, Hunt–Hess score, fever, mechanical ventilation, phenylephrine dose, and time from SAH symptom onset),12-14 whereas other studies reported no effects.1518 This study further demonstrates that troponin levels are elevated after SAH and confirms the association between cTn elevation and outcome after SAH. As we were unable to make adjustments for covariates because of the lack of individual patient data, this study did not address cause–effect relationships. Of the various known biochemical markers, cTn is a more sensitive and specific marker of myocardial injury after SAH than creatine kinase MB fraction.8,9 cTn elevation is positively correlated with regional WMA.3,11,39 Compared with control patients with myocardial infarction, SAH patients with stunned myocardia tend to show substantially lower peak cTnI, given the same magnitude of left ventricular systolic dysfunction by echocardiography.40 Serial echocardiographic examinations revealed direct impairment of regional cardiac contractility during the acute phase of SAH. Indeed, transient regional WMAs after SAH showed a similar enough pattern to meet the criteria for transient left ventricular apical ballooning syndrome.34,41 cTnI leaks are associated with the severity of SAH (Hunt–Hess scale),3,8,10,25,39 and these typically peak within 2 days after ictus, with a subsequent decay in levels.3,10 Naidech et al10 reported that troponin elevation

L. ZHANG ET AL.

6

Figure 2.

The pooled RRs of cTn elevation for outcome measures. Abbreviations: cTn, cardiac troponin; RRs, risk ratios.

(categorized into quintiles) was significantly associated with an increased likelihood of poor outcome (as measured by a modified Rankin Scale score of 4-6) at discharge and at 3 months. In this respect, the presence

and degree of cardiac abnormality may influence outcome, and therefore, the degree of troponin elevation has been associated with poor outcome. However, after adjusting for age, clinical grade, and aneurysm size, this

Figure 3. The pooled RRs of cTn elevation for outcome measures at 3and 12-month follow-ups. Abbreviations: cTn, cardiac troponin; RRs, risk ratios.

CARDIAC TROPONIN ELEVATION AND OUTCOME AFTER SAH

Figure 4.

7

The pooled RRs of cTn elevation for outcome measures at in-hospital follow-ups. Abbreviations: cTn, cardiac troponin; RRs, risk ratios.

positive association was significant at discharge, but not at 3 months. The impact of cardiac damage on functional outcome is likely related to its effects on the management of cerebral vasospasm and the resultant DCI. Left ventricular dysfunction may directly affect cerebral perfusion, a potential explanation for the finding that cardiac abnormalities are also correlated with DCI. DCI occurs unpredictably in approximately 30% of patients at 4-12 days after the initial hemorrhage42 and is an important contributor to poor outcome. Many patients with SAH have narrowed arteries and hypovolemia, and autoregulation of cerebral perfusion is disturbed after SAH.43,44 Furthermore, the duration of loss of consciousness at the time of ictus, the total amount of extravasated blood,45 and the occurrence of hypovolemia and hypotension46 are powerful and independent predictors of DCI. The pathogenesis of DCI is often attributed to vasospasm of the intracranial arteries.47 However, vasospasm cannot be the only initiator of DCI, as vasospasm is not observed in one third of patients with DCI, and DCI does not develop in one third of patients with severe vasospasm.48 As described previously,49 several novel pathological mechanisms,

including microthrombosis, cortical spreading depression, and damage to cerebral tissue during the first 72 hours after aneurysm rupture (ie, ‘‘early brain injury’’), have been suggested to contribute to DCI. In the present study, we established an association between cTn elevation and DCI after SAH. These results should be interpreted with caution, as this study has several shortcomings. First, the inclusion of 2 retrospective studies in a review is notable, as there is a high risk of biased data collection in retrospective observational studies. Second, the included studies were published over a period of 14 years. During this period, case fatality rates have decreased because the diagnosis and treatment of SAH have improved,50 potentially affecting the prevalence and consequence of cardiac complications on outcomes. Third, the baseline characteristics of the included studies and the prevalence of cTn elevation and outcomes showed large variations, suggesting differences in study populations that could influence our results. Finally, without adjustments for covariates because of the lack of individual patient data, the relationship between cTn elevation and outcome may be overstated. The heterogeneity in the timing of the assessment, the different

Figure 5. The pooled RRs of cTn elevation for SAH severity by poor condition on admission. Abbreviations: cTn, cardiac troponin; RRs, risk ratios; SAH, subarachnoid hemorrhage.

L. ZHANG ET AL.

8

Figure 6.

The pooled RRs of SAH severity for outcome measures. Abbreviations: RRs, risk ratios; SAH, subarachnoid hemorrhage.

clinical severity scores, and thresholds used to dichotomize the various scales are also complicating factors. The shortcomings of this meta-analysis and the included studies highlight the need for large, prospective, observational studies with clearly defined methodology, sufficient sample sizes, and long-term follow-ups to accurately determine whether cTn elevation has independent prognostic value after SAH. This study was a systemic review and meta-analysis on observational studies. Therefore, we only assessed associations, and pathophysiological pathways and therapeutic hypotheses were not evaluated. Further study will be required to establish the independent prognostic value of elevated troponin and to elucidate the pathophysiological mechanisms.

Conclusions In conclusion, our findings supported an association between cTn elevation after SAH and an increased risk of DCI, poor outcome, and death. Acknowledgment: We are grateful to our colleagues (YuyingXie, Wei Yu, and Ying Wang) for their advice. This project was supported by grants from the Natural Science Foundation of China (No. 81271456). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References 1. van Gijn J, Kerr RS, Rinkel GJE. Subarachnoid haemorrhage. Lancet 2007;369:306-318. 2. van der Bilt IA, Hasan D, Vandertop WP, et al. Impact of cardiac complications on outcome after aneurysmal subarachnoid hemorrhage: a meta-analysis. Neurology 2009; 62:635-642. 3. Tung P, Kopelnik A, Banki N, et al. Predictors of neurocardiogenic injury after subarachnoid hemorrhage. Stroke 2004;35:548-551. 4. Banki NM, Kopelnik A, Dae MW, et al. Acute neurocardiogenic injury after subarachnoid hemorrhage. Circulation 2005;112:3314-3319. 5. Kono T, Morita H, Kuroiwa T, et al. Left ventricular wall motion abnormalities in patients with subarachnoid hemorrhage: neurogenic stunned myocardium. J Am Coll Cardiol 1994;24:636-640. 6. Murthy SB, Shah S, Rao CP, et al. Neurogenic stunned myocardium following acute subarachnoid hemorrhage: pathophysiology and practical considerations. J Intensive Care Med 2013 [Epub ahead of print]. 7. de Lemos JA. Increasingly sensitive assays for cardiac troponins: a review. JAMA 2013;309:2262-2269. 8. Parekh N, Venkatesh B, Cross D, et al. Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage. J Am Coll Cardiol 2000; 36:1328-1335. 9. Deibert E, Barzilai B, Braverman AC, et al. Clinical significance of elevated troponin I levels in patients with nontraumatic subarachnoid hemorrhage. J Neurosurg 2003; 98:741-746. 10. Naidech AM, Kreiter KT, Janjua N, et al. Cardiac troponin elevation, cardiovascular morbidity, and outcome after

CARDIAC TROPONIN ELEVATION AND OUTCOME AFTER SAH

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21. 22.

23.

24.

25.

26.

27.

28.

subarachnoid hemorrhage. Circulation 2005; 112:2851-2856. Hravnak M, Frangiskakis JM, Crago EA, et al. Elevated cardiac troponin I and relationship to persistence of electrocardiographic and echocardiographic abnormalities after aneurysmal subarachnoid hemorrhage. Stroke 2009;40:3478-3484. Yarlagadda S, Rajendran P, Miss JC, et al. Cardiovascular predictors of in-patient mortality after subarachnoid hemorrhage. Neurocrit Care 2006;5:102-107. Mayer SA, Lin J, Homma S, et al. Myocardial injury and left ventricular performance after subarachnoid hemorrhage. Stroke 1999;30:780-786. Kawasaki T, Azuma A, Sawada T, et al. Electrocardiographic score as a predictor of mortality after subarachnoid hemorrhage. Circ J 2002;66:567-570. Schuiling WJ, Algra A, de Weerd AW, et al. ECG abnormalities in predicting secondary cerebral ischemia after subarachnoid haemorrhage. Acta Neurochir (Wien) 2006;148:853-858. Zaroff JG, Rordorf GA, Newell JB, et al. Cardiac outcome in patients with subarachnoid hemorrhage and electrocardiographic abnormalities. Neurosurgery 1999; 44:34-39. Sakr YL, Lim N, Amaral AC, et al. Relation of ECG changes to neurological outcome in patients with aneurysmal subarachnoid hemorrhage. Int J Cardiol 2004; 96:369-373. Schuiling WJ. Troponin I in predicting cardiac or pulmonary complications and outcome in subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2005; 76:1565-1569. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968;28:14-20. Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg 1988;68:985-986. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:81-84. Botterell EH, Lougheed WM, Scott JW, et al. Hypothermia, and interruption of carotid, or carotid and vertebral circulation, in the surgical management of intracranial aneurysms. J Neurosurg 1956;13:1-42. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available at: http://www.cochrane-handbook.org. Accessed 10 January 2014. van der Bilt I, Hasan D, van den Brink R, et al. Cardiac dysfunction after aneurysmal subarachnoid hemorrhage: relationship with outcome. Neurology 2014;82:1-8. Ramappa P, Thatai D, Coplin W, et al. Cardiac troponin-I: a predictor of prognosis in subarachnoid hemorrhage. Neurocrit Care 2008;8:398-403. Sandhu R, Aronow WS, Rajdev A, et al. Relation of cardiac troponin I levels with in-hospital mortality in patients with ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Am J Cardiol 2008; 102:632-634. Miketic JK, Hravnak M, Sereika SM, et al. Elevated cardiac troponin I and functional recovery and disability in patients after aneurysmal subarachnoid hemorrhage. Am J Crit Care 2010;19:522-528. Degos V, Apfel CC, Sanchez P, et al. An admission bioclinical score to predict 1-year outcomes in patients undergoing aneurysm coiling. Stroke 2012;43:1253-1259.

9

29. Gupte M, John S, Prabhakaran S, et al. Troponin elevation in subarachnoid hemorrhage does not impact in-hospital mortality. Neurocrit Care 2013;18:368-373. 30. Yuki K, Kodama Y, Onda J, et al. Coronary vasospasm following subarachnoid hemorrhage as a cause of stunned myocardium: case report. J Neurosurg 1991;75:308-311. 31. Junttila E, Vaara M, Koskenkari J, et al. Repolarization abnormalities in patients with subarachnoid and intracerebral hemorrhage: predisposing factors and association with outcome. Anesth Analg 2013;116:190-197. 32. Mayer SA, LiMandri G, Homma S, et al. Electrocardiographic markers of abnormal left ventricular wall motion in acute subarachnoid hemorrhage. J Neurosurg 1995; 83:889-896. 33. Zaroff JG, Rordorf GA, Ogilvy CS, et al. Regional patterns of left ventricular systolic dysfunction after subarachnoid hemorrhage: evidence for neurally mediated cardiac injury. J Am Soc Echocardiogr 2000;13:774-779. 34. Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N.Engl J Med 2005;352:539-548. 35. Sugimoto K, Inamasu J, Hirose Y, et al. The role of norepinephrine and estradiol in the pathogenesis of cardiac wall motion abnormality associated with subarachnoid hemorrhage. Stroke 2012;43:1897-1903. 36. Apple FS. Tissue specificity of cardiac troponin I, cardiac troponin T and creatine kinase-MB. Clin Chim Acta 1999; 284:151-159. 37. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation 2012; 126:2020-2035. 38. Turck N, Vutskits L, Sanchez-Pena P, et al. A multiparameter panel method for outcome prediction following aneurysmal subarachnoid hemorrhage. Intensive Care Med 2006;36:107-115. 39. Tanabe M, Crago EA, Suffoletto MS, et al. Relation of elevation in cardiac troponin I to clinical severity, cardiac dysfunction, and pulmonary congestion in patients with subarachnoid hemorrhage. Am J Cardiol 2008; 102:1545-1550. 40. Bulsara KR, McGirt MJ, Liao L, et al. Use of the peak troponin value to differentiate myocardial infarction from reversible neurogenic left ventricular dysfunction associated with aneurysmal subarachnoid hemorrhage. J Neurosurg 2003;98:524-528. 41. Lee VH, Connolly HM, Fulgham JR, et al. Tako-tsubo cardiomyopathy in aneurysmal subarachnoid hemorrhage: an underappreciated ventricular dysfunction. J Neurosurg 2006;105:264-270. 42. Brilstra EH, Rinkel GJ, Algra A, et al. Rebleeding, secondary ischemia, and timing of operation in patients with subarachnoid hemorrhage. Neurology 2000;55:1656-1660. 43. Lang EW, Diehl RR, Mehdorn HM. Cerebral autoregulation testing after aneurysmal subarachnoid hemorrhage: the phase relationship between arterial blood pressure and cerebral blood flow velocity. Crit Care Med 2001;29:158-163. 44. Soehle M, Czosnyka M, Pickard JD, et al. Continuous assessment of cerebral autoregulation in subarachnoid hemorrhage. Anesth Analg 2004;98:1133-1139. 45. Hop JW, Rinkel GJE, Algra A, et al. Initial loss of consciousness and risk of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Stroke 1999; 30:2268-2271. 46. Chang HS, Hongo K, Nakagawa H. Adverse effects of limited hypotensive anesthesia on the outcome of patients with subarachnoid hemorrhage. J Neurosurg 2000;92:971-975.

10 47. Uekusa H, Miyazaki C, Kondo K, et al. Hydroperoxide in internal jugular venous blood reflects occurrence of subarachnoid hemorrhage-induced delayed cerebral vasospasm. J Stroke Cerebrovasc Dis 2014;23:2217-2224. 48. Rabinstein AA, Friedman JA, Weigand SD, et al. Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 2004;35:1862-1866.

L. ZHANG ET AL. 49. Rowland MJ, Hadjipavlou G, Kelly M, et al. Delayed cerebral ischaemia after subarachnoid haemorrhage: looking beyond vasospasm. Br J Anaesth 2012;109:315-329. 50. Nieuwkamp DJ, Setz LE, Algra A, et al. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol 2009;8:635-642.