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Clinical Importance of Cardiac Troponin Release and Cardiac Abnormalities in Patients With Supratentorial Cerebral Hemorrhages
ORIGINAL ARTICLE TROPONIN AND CARDIAC ABNORMALITIES IN ICH PATIENTS
Clinical Importance of Cardiac Troponin Release and Cardiac Abnormalities in Patients With Supratentorial Cerebral Hemorrhages BOBY V. MARAMATTOM, MD, DM; EDWARD M. MANNO, MD; JIMMY R. FULGHAM, MD; ALLAN S. JAFFE, MD; AND EELCO F. M. WIJDICKS, MD OBJECTIVE: To determine the incidence of cardiac troponin T (cTnT) elevation, electrocardiographic (ECG) changes, and arrhythmias in supratentorial intracerebral hemorrhage (ICH) and their association with early mortality. PATIENTS AND METHODS: Patients with supratentorial ICHs admitted to Mayo Clinic, Rochester, Minn, from March 1998 to October 2003 were studied. We excluded moribund patients with ICHs who died within 12 hours of hospital admission. Cardiac troponin T levels measured on admission and day 2 were determined by a third-generation enzyme-linked immunosorbent assay. Continuous ECG monitoring was performed in all patients. Computed tomographic scans were graded and correlated with abnormal cardiac variables. RESULTS: Peak levels of cTnT were elevated at 0.035 to 1.2 µg/L (mean ± SD, 0.27±0.38 µg/L) in 10 (20%) of 49 patients and were not associated with changes in creatine kinase MB fraction or ECG results. The cTnT levels did not correlate with location or side of hemorrhage or mortality at 30 days. Seventy (64%) of 110 patients displayed ECG abnormalities. The ECG changes did not correlate with the location or side of ICH, hydrocephalus, midline shift, or extension to the ventricles. CONCLUSION: The cTnT elevations in survivors of acute ICH are frequent but without confirmatory ECG changes that suggest mild myocardial injury. One-month mortality is not influenced by such cTnT elevations. In addition, ECG abnormalities are common but likely benign in patients with supratentorial ICH who survive the initial insult.
Mayo Clin Proc. 2006;81(2):192-196 cTnI = cardiac troponin I; cTnT = cardiac troponin T; ECG = electrocardiograpic; ICH = intracerebral hemorrhage; NICU = neurologic intensive care unit; SAH = subarachnoid hemorrhage
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ardiac troponin T (cTnT) and cardiac troponin I (cTnI) are currently the tests of choice for detection of myocardial injury.1 The presence of elevated values of cardiac troponins in patients with acute neurologic diseases has been associated with an adverse prognosis. In a study of a heterogeneous group of patients with strokes, head injuries, and seizures, elevations in cTnI levels were observed in 19% of patients and correlated with poor prognosis.2 If this is also the case with intracerebral hemorrhage (ICH), then criteria for continued neurologic intensive care unit (NICU) observation should include elevated troponin values and cardiac arrhythmias. Several studies have examined the incidence and importance of cardiac troponins, cardiac arrhythmias, and electrocardiographic (ECG) changes in ischemic stroke and subarachnoid hemorrhage (SAH),3-7 but data in patients with ICHs are insufficient. 192
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We sought to define the incidence of these abnormalities and the importance of these findings to early mortality in a homogeneous group of patients with spontaneous ICHs. PATIENTS AND METHODS Data from patients with supratentorial ICH admitted to the Saint Marys Hospital NICU, Mayo Clinic, Rochester, Minn, from March 1998 to October 2003 were reviewed. We included patients with lobar, thalamic, and capsuloganglionic bleeds. The level of consciousness was graded on admission using the Glasgow Coma Scale. All patients underwent continuous ECG monitoring, blood pressure recording, and oxygen saturation monitoring. Rhythm disturbances recorded on paper strips were available later for review. A standard 12-lead ECG was performed at admission; additional ECGs were obtained if there were abnormalities in rhythm or morphology. Cardiologists interpreted all ECGs. We excluded moribund patients from the study, defined as those who died within 12 hours of admission, because comprehensive data were not available for these patients. Other exclusionary criteria were ICH secondary to trauma, primary or secondary tumors, vascular malformations, thrombolytic agents, and drug abuse. One patient with clinical myocardial infarction was excluded from the analysis. Agonal or terminal ECG patterns were also excluded from ECG analyses. Electrocardiographic findings and data from patients with prior ischemic heart disease or those taking cardioactive drugs such as β-blockers, calcium channel blockers, and inotropics were analyzed separately. A history of diabetes mellitus, hypertension, tobacco use, alcohol use, pulmonary disease, ischemic heart disease, renal failure, and seizures and prior medications were recorded for all patients. Cardiac troponin T levels were From the Department of Neurology and Division of Critical Care Neurology (B.V.M., E.M.M., J.R.F., E.F.M.W.) and Division of Cardiovascular Diseases (A.S.J.), Mayo Clinic College of Medicine, Rochester, Minn. Dr Maramattom is now with Lourdes Hospital, Vaduthala, Kochi, Kerala, India. Individual reprints of this article are not available. Address correspondence to Eelco F. M. Wijdicks, MD, Department of Neurology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2006 Mayo Foundation for Medical Education and Research
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TROPONIN AND CARDIAC ABNORMALITIES IN ICH PATIENTS
tained using the JMP statistical software, version 5.0.1.2 (SAS Institute Inc, Cary, NC). Log rank tests were used for comparison of survival curves.
TABLE 1. Demographics and Clinical Characteristics of 75 Patients With ICH and Measured cTnT Values* No. (%) of patients
Sex
Male Female Medical history Diabetes Hypertension Prior cardiac illness Level of consciousness GCS score 3-7 GCS score 8-15 Location Lobar Frontal Temporal Parietal Occipital Extensive Ganglionic Thalamic Internal capsule Right Left CT location Subarachnoid extension of ICH Intraventricular extension of ICH Hydrocephalus Midline shift Outcome Dead
Group 1 (cTnT ≤0.035 µg/L) (n=39)
Group 2 (cTnT >0.035 µg/L) (n=10)
20 (51) 19 (49)
4 (40) 6 (60)
7 (18) 28 (72) 10 (26)
3 (30) 7 (70) 5 (50)
14 (36) 25 (64)
5 (50) 5 (50)
P value
RESULTS
.75
PATIENT CHARACTERISTICS There were 122 patients with supratentorial ICHs. Twelve moribund patients with primary ICH were excluded from the study because of incomplete data, leaving a study population of 110 patients. Patients ranged in age from 20 to 92 years (mean age, 71 years), and 55% were male. The location of the ICH was lobar in 60 patients, ganglionic in 30, thalamic in 17, internal capsule in 2, and bilateral in 1 patient. Right-sided ICH occurred in 65 patients (59%) and left-sided ICH in 45 patients (41%). Intraventricular extension of ICH was seen in 50 patients, and subarachnoid extension was found in 22 patients. Twenty-six patients underwent cTnI assays before August 2000, the results of which were normal in all patients. Fifty patients underwent the cTnT assay. In 30 patients, follow-up cTnT values were available. These patients were subdivided into 2 groups: group 1 had values of 0.035 µg/mL or less (39 patients), and group 2 had levels greater than 0.035 µg/mL (11 patients) (Table 1). Figure 1 details the final sample size.
.22 .11 .25 .47 .22
19 (49) 5 (13) 3 (8) 3 (8) 0 (0) 8 (21) 11 (28) 8 (21) 1 (2) 21 (54) 18 (46)
8 (80) 3 (30) 3 (30) 0 (0) 1 (10) 1 (10) 2 (20) 0 (0) 0 (0) 7 (70) 3 (30)
.15 .95 .49 .49 .20 .40 .46 .13 .79 .48 .29
11 (28)
3 (30)
.78
23 (59) 12 (31) 13 (33)
5 (50) 2 (20) 6 (60)
.72 .89 .16
16 (41)
2 (20)
.25
CARDIAC TROPONIN T Admission cTnT levels were elevated in 10 (20%) of 49 patients (95% confidence interval, 10-32). Elevations were modest (range, 0.035-1.2 µg/L; mean ± SD, 0.27±0.38 µg/L).
*The mean age of the patients was 73 years in group 1 and 63 years in group 2. CT = computed tomography; cTnT = cardiac troponin T; GCS = Glasgow Coma Scale; ICH = intracer ebral hemorrhage.
110 Study patients
determined on admission and on day 2 with a third-generation enzyme-linked immunosorbent assay (Roche, Basel, Switzerland). The 99th percentile with that assay and the 10% coefficient of variation are less than 0.01 µg/L and 0.035 µg/L, respectively.8 Before August 2000, assays were performed for cTnI (upper reference range of which was 0.5 ng/mL). Computed tomography was performed on admission or if there was any change in clinical status. Location of ICH, volume, subarachnoid or intraventricular presence of blood, hydrocephalus, and midline shift were noted. Midline shift was measured in millimeters at the level of the pineal gland and the septum pellucidum. Follow-up records were reviewed, and both 30- and 60-day mortality were recorded. Continuous variables were compared by unpaired t tests. Two or more categorical variables were analyzed by the χ2 test and Fisher exact test. All statistical analyses, including Kaplan-Meier survivor analysis curves, were obMayo Clin Proc.
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76 Troponin assay
26 cTnI assay normal levels
34 No troponin assay
50 cTnT assay
39 Group 1 10 Group 2 normal levels abnormal levels
1 Clinical MI*
FIGURE 1. Sample size depiction of patients undergoing analysis for troponin elevation. cTnI = cardiac troponin I; cTnT = cardiac troponin T; MI = myocardial infarction. *Patient excluded from analysis.
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dysfunction. No correlation of cTnT was seen with location (Table 1), volume, and side of hemorrhage (P=.48), hydrocephalus (P=.89), extraparenchymal extension (P=.15), or midline shift (P=.16). The cTnT elevations remained common in patients with and without preexisting cardiac illness or other cardiovascular risk factors. Only 2 deaths occurred in this group in the first 60 days compared with 16 deaths in group 1. Sixty-day survival curves showed no difference between the 2 groups (P=.47) (Figure 2).
1.0
Survival
0.8 0.6 0.4
Group 1 (cTnT levels ≤0.035 µg/L) Group 2 (cTnT levels >0.035 µg/L)
0.2 0.0 0
5
10
15
20
25
30
Time to death (d)
FIGURE 2. Kaplan-Meier 60-day survival curves show no significant differences in survival between the 2 groups (P=.47).
These patients did not have a concomitant creatine kinase MB fraction elevation. One additional patient had a myocardial infarction diagnosed clinically with ECG changes of infarction. The cTnT level in this patient was 2.32 µg/L. This patient was excluded from the final analysis. Additional measurements of cTnT were available in 6 patients on day 2. This group also was not different clinically from the overall group. Twenty-four patients from group 2 also did not show further increases. The cTnT elevation was not associated with new-onset ECG changes on ECGs obtained either at admission or at 24 hours (P=.32). Patients without cTnT elevation showed similar ECG changes. Echocardiograms were performed in 6 patients with troponin elevations and showed no regional wall motion abnormalities or left ventricular TABLE 2. Types of ECG Changes in 110 Patients With Intracerebral Hemorrhage* ECG changes
No. (%) of patients
Sinus bradycardia Sinus tachycardia PSVC PVC SVT Atrial fibrillation or flutter Ectopic atrial rhythms, MAT, or PAT Junctional tachycardia QTc prolongation First-degree heart block RBBB ST-T morphologic changes LAFB Total
11 (10) 5 (4) 7 (6) 12 (11) 1 (1) 13 (12) 6 (5) 1 (1) 8 (7) 14 (13) 8 (7) 15 (14) 5 (4) 70 (64)
*ECG = electrocardiographic; LAFB = left anterior fascicular block; MAT = multifocal atrial tachycardia; PAT = paroxysmal atrial tachycardia; PSVC = premature supraventricular complexes; PVC = premature ventricular complex; QTc = corrected QT interval; RBBB = right bundle branch block; SVT = supraventricular tachycardia.
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ECG CHANGES All 110 patients had ECG recordings available for review. Changes in ECGs were seen in 70 patients (64%) (95% confidence interval, 54-72). Rhythm abnormalities were commonly seen (69%), even when patients with prior heart disease or previously documented ECG abnormalities were excluded. The common rhythm abnormalities were episodic sinus bradycardia, ventricular premature contractions, atrial fibrillation, and first-degree heart block (Table 2). Changes in ECGs were seen in 60 patients in the first 4 days and in 10 patients after 4 days. No life-threatening arrhythmias or ECG changes were seen during monitoring in the NICU. Major arrhythmias were defined as those requiring medical intervention or causing hemodynamic compromise. Major arrhythmias that required medical intervention occurred only in 1 patient and comprised a supraventricular tachycardia. ST-T planar segment changes that resembled ischemia were seen in 3 patients without concomitant cardiac marker changes and returned to normal on follow-up. All major ECG changes occurred only in right-sided ICH (P=.50). Mortality was not related to ECG changes (P=.27) (Table 3). After using unpaired t tests to compare proportions between groups with normal and elevated cTnT levels, ECG changes were not found to be correlated with elevated cTnT levels (P=.22) (Table 3). DISCUSSION Both cTnT and cTnI are currently considered the gold standard for detection of myocardial injury. The European Society of Cardiology and American College of Cardiology guidelines have suggested that levels above the 99th percentile be considered abnormal if they can be measured with 10% coefficient of variation. When these criteria are not met, it is suggested that the lowest value with a 10% coefficient of variation be used.8 This value is 0.035 µg/L for cTnT.8 Data on cTnT levels are not available in patients with ICH. In our homogeneous group of patients, modest elevations of cTnT levels (0.035-1.2 µg/L) were observed, but short-term prognosis did not appear to be influenced.
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TROPONIN AND CARDIAC ABNORMALITIES IN ICH PATIENTS
However, we only measured troponin levels in patients for 2 days and had only 30-day follow-up. Nevertheless, our data provide guidance for the clinical management of such patients during the acute phase of their illness. The most recent studies of patients with SAH have shown elevations of cardiac troponin levels in 17% to 28% of patients associated with left ventricular dysfunction clinically and on echocardiography.9-11 Some studies have shown an absence of a relationship between elevations of troponin levels and the clinical grade or amount of blood in patients,9,10 although other studies have established a close relationship between severe grades of SAH and cTnI elevation.11 It is thought that in addition to occult coronary artery disease, catecholamines may also mediate myocardial injury in patients with SAH. Increased intracranial pressure leads to marked release of catecholamines, which can induce tachycardia, coronary vasospasm, coronary and peripheral vasoconstriction, and direct myocardial toxicity due to increased intracellular calcium. In patients with stroke of varied origin, troponin elevations occurred in roughly 17% and were associated with an adverse prognosis over time.12 It is not surprising that our results clash with prior studies on SAH and stroke. There are some reasons for this discrepancy. First, series including patients with ischemic stroke12 have included those with a high frequency of cardioembolism (15%-20%) and ischemic heart disease, thus increasing the likelihood of troponin elevation and mortality. Second, elevated troponin levels and cutoff values were defined only in 2002.8 The major studies on the importance of troponin levels9,11,12 were conducted before this definition and used different cutoff values for cTnI or cTnT. Thus, we used well-defined cutoff levels for cTnT that were lower than those used in the literature, picking up even minor degrees of cardiac injury. However, we still could not discern a relationship between elevated cTnT levels and any of the neurologic variables such as location, side of hemorrhage, extraparenchymal extension, hydrocephalus, or midline shift. Third, we studied a homogeneous population in contrast to studies of patients with ischemic stroke. Moreover, our series cannot be compared with patients with SAHs who tend to have higher catecholamine surges and thus are likely to have higher troponin levels. Nevertheless, because of the nature of our study and exclusion of moribund patients, we may have excluded a group that likely would have shown cTnT elevations in the acute phase and assisted in establishing the relationship to mortality. Recent studies have shown elevation of cTnT levels in noncardiac conditions, such as pulmonary embolism, lobar pneumonia, acute heart failure, and end-stage renal disease.8,13-15 One could argue that we inadvertently Mayo Clin Proc.
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TABLE 3. Comparison of ECG Data and Mortality in Patients With or Without Increased Levels of cTnT* No. (%) of patients
ECG variable Atrial fibrillation RBBB ST-T planar changes Prolonged QT PVC Sinus tachycardia Mortality
Group 1 (cTnT ≤0.035 µg/L) (n=39)
Group 2 (cTnT >0.035 µg/L) (n=10)
P value
3 (8) 3 (8)
0 2 (20)
.54 .21
7 (18) 5 (13) 5 (13)
2 (20) 0 2 (20)
.52 .35 .36
2 (5) 16 (50)
2 (20) 2 (20)
.36 .27
*The total number of ECG changes was 32 in group 1 and 7 in group 2 (P=.32). cTnT = cardiac troponin T; ECG = electrocardiographic; PVC = premature ventricular complex; RBBB = right bundle branch block.
included patients with such conditions, which manifest prognostic importance. However, although end-stage renal disease may predispose to elevations in troponin levels, in our study only 2 such patients among the group had elevated troponin values. We believe that pragmatically clinicians would be more interested in the importance of troponin levels of patients who are likely to survive the first 24 hours of an ICH because the moribund group would have a poor prognosis. The results of our ECG and rhythm analysis are similar to those observed with troponin. It is well known that cardiac arrhythmias occur in cerebrovascular accidents, primarily ischemic strokes, and SAHs due to alterations in autonomic tone.1,2,4-7 Subarachnoid hemorrhage in particular induces a wide variety of ECG changes, such as QT prolongation, changes of ischemia, and life-threatening arrhythmias such as ventricular fibrillation or flutter and occasionally torsade de pointes.16-18 Two mechanisms are postulated: autonomic neural stimulation from the hypothalamus and elevated circulating catecholamines.6 Ischemic stroke also induces a wide array of cardiac arrhythmias. Right hemispheric strokes are more arrhythmogenic than are left-sided ones,1 and involvement of the insular cortex (frequently involved in middle cerebral artery stroke) predisposes patients to sudden cardiac death. Other locations implicated in the genesis of ECG changes include parts of the central autonomic network such as the amygdala and lateral hypothalamus. Heart rate variability, which has a circadian rhythm, may be reversibly abolished in the acute phase of ischemic stroke, further predisposing patients to arrhythmias and cardiac death.2,7 The literature that pertains to ECG abnormalities in patients with ICHs is limited, with only a few articles and small numbers of patients.19-22 Intracerebral hematomas can induce repolarization abnormalities, QT prolongation, neu-
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rogenic T waves, and supraventricular arrhythmias. The incidence of ECG abnormalities has been found to be as high as 92.3%. Right hemispheric hematomas have been associated with supraventricular arrhythmias, specifically atrial extrasystoles, in small numbers of patients. Sudden cardiac death has also been seen, with a possible relationship to left hemispheric hematomas.10 Noncardiogenic pulmonary edema and spontaneous atrial fibrillation have been reported with brainstem hematomas.11 The proposed mechanism of ECG abnormalities is thought to be alterations in autonomic tone mediated by fibers projecting to the heart via the stellate ganglia. We found ECG abnormalities to be common in patients with ICHs (64%). However, most abnormalities were minor arrhythmias or morphologic changes, which did not require medical intervention and did not seem to be associated with increased mortality. Contrary to other studies, we did not find any correlation between hemorrhage localization and ECG changes. We found ECG changes suggestive of myocardial ischemia without concomitant troponin elevations, analogous to the changes in SAH suggestive of alterations in autonomic tone. In agreement with many recent studies of SAH, we found a lack of contribution of ECG changes to mortality.23,24 In our group of patients, the lack of life-threatening ECG changes could be attributed to the exclusion of moribund patients and the relatively low prevalence of coma (70% of our patients had a Glasgow Coma Scale score >8). Patients with sinus tachycardia or bundle branch block tended to manifest elevated cTnT levels, but, because of the small sample size, these interactions were not statistically significant. CONCLUSION We conclude that patients with supratentorial ICH may manifest mild or modest elevations of cTnT levels. This represents subclinical myocardial injury due to acute ICH when clinical or ECG manifestations of myocardial ischemia or left ventricular dysfunction are absent. Such elevations of cTnT levels do not influence the early outcome of patients. Prolonged observation in the NICU is not warranted. REFERENCES 1. Adams JE III, Bodor GS, Davila-Roman VG, et al. Cardiac troponin I: a marker with high specificity for cardiac injury. Circulation. 1993;88:101-106. 2. Dixit S, Castle M, Velu RP, Swisher L, Hodge C, Jaffe AS. Cardiac involvement in patients with acute neurologic disease: confirmation with cardiac troponin I. Arch Intern Med. 2000;160:3153-3158.
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3. Tokgözoglu SL, Batur MK, Topçuoglu MA, Saribas O, Kes S, Oto A. Effects of stroke localization on cardiac autonomic balance and sudden death. Stroke. 1999;30:1307-1311. 4. Korpelainen JT, Sotaniemi KA, Huikuri HV, Myllyla VV. Circadian rhythm of heart rate variability is reversibly abolished in ischemic stroke. Stroke. 1997;28:2150-2154. 5. Naver HK, Blomstrand C, Wallin BG. Reduced heart rate variability after right-sided stroke. Stroke. 1996;27:247-251. 6. Masson C, Lehericy S, Cohen Solal A, Verstichel P, Masson M. Electrocardiographic anomalies in relation with infarction in the territory of the anterior choroid artery [in French]. Rev Neurol (Paris). 1995;151:670673. 7. Davis TP, Alexander J, Lesch M. Electrocardiographic changes associated with acute cerebrovascular disease: a clinical review. Prog Cardiovasc Dis. 1993;36:245-260. 8. Apple FS, Wu AH, Jaffe AS. European Society of Cardiology and American College of Cardiology guidelines for redefinition of myocardial infarction: how to use existing assays clinically and for clinical trials. Am Heart J. 2002;144:981-986. 9. Horowitz MB, Willet D, Keffer J. The use of cardiac troponin-I (cTnI) to determine the incidence of myocardial ischemia and injury in patients with aneurysmal and presumed aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien). 1998;140:87-93. 10. 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. 11. 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. 12. James P, Ellis CJ, Whitlock RM, McNeil AR, Henley J, Anderson NE. Relation between troponin T concentration and mortality in patients presenting with an acute stroke: observational study. BMJ. 2000;320:1502-1504. 13. Pruszczyk P, Bochowicz A, Torbicki A, et al. Cardiac troponin T monitoring identifies high-risk group of normotensive patients with acute pulmonary embolism. Chest. 2003;123:1947-1952. 14. Freda BJ, Tang WH, Van Lente F, Peacock WF, Francis GS. Cardiac troponins in renal insufficiency: review and clinical implications. J Am Coll Cardiol. 2002;40:2065-2071. 15. Weinberg I, Cukierman T, Chajek-Shaul T. Troponin T elevation in lobar lung disease. Postgrad Med J. 2002;78:244-245. 16. Fukui S, Katoh H, Tsuzuki N, et al. Multivariate analysis of risk factors for QT prolongation following subarachnoid hemorrhage. Crit Care. 2003;7: R7-R12. 17. Randell T, Tanskanen P, Scheinin M, Kytta J, Ohman J, Lindgren L. QT dispersion after subarachnoid hemorrhage. J Neurosurg Anesthesiol. 1999;11: 163-166. 18. Lanzino G, Kongable GL, Kassell NF. Electrocardiographic abnormalities after nontraumatic subarachnoid hemorrhage. J Neurosurg Anesthesiol. 1994;6:156-162. 19. Chao CL, Chen WJ, Wu CC, Lee YT. Torsade de pointes and T-wave alternans in a patient with brainstem hemorrhage. Int J Cardiol. 1995;51:199201. 20. Serrano-Castro V, Gil-Peralta A, Gonzalez-Marcos JR, Moreno-Rojas A, Pedrote A, Errazquin P. Cardiac disease in intracerebral hematomas [in Spanish]. Rev Neurol. 1998;26:800-803. 21. Yamour BJ, Sridharan MR, Rice JF, Flowers NC. Electrocardiographic changes in cerebrovascular hemorrhage. Am Heart J. 1980;99:294-300. 22. Arruda WO, de Lacerda Junior FS. Electrocardiographic findings in acute cerebrovascular hemorrhage: a prospective study of 70 patients. Arq Neuropsiquiatr. 1992;50:269-274. 23. Brouwers PJ, Wijdicks EF, Hasan D, et al. Serial electrocardiographic recording in aneurysmal subarachnoid hemorrhage. Stroke. 1989;20:11621167. 24. Zaroff JG, Rordorf GA, Newell JB, Ogilvy CS, Levinson JR. Cardiac outcome in patients with subarachnoid hemorrhage and electrocardiographic abnormalities. Neurosurgery. 1999;44:34-39.
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Clinical Importance of Cardiac Troponin Release and Cardiac Abnormalities in Patients With Supratentorial Cerebral Hemorrhages BOBY V. MARAMATTOM, MD, DM; EDWARD M. MANNO, MD; JIMMY R. FULGHAM, MD; ALLAN S. JAFFE, MD; AND EELCO F. M. WIJDICKS, MD OBJECTIVE: To determine the incidence of cardiac troponin T (cTnT) elevation, electrocardiographic (ECG) changes, and arrhythmias in supratentorial intracerebral hemorrhage (ICH) and their association with early mortality. PATIENTS AND METHODS: Patients with supratentorial ICHs admitted to Mayo Clinic, Rochester, Minn, from March 1998 to October 2003 were studied. We excluded moribund patients with ICHs who died within 12 hours of hospital admission. Cardiac troponin T levels measured on admission and day 2 were determined by a third-generation enzyme-linked immunosorbent assay. Continuous ECG monitoring was performed in all patients. Computed tomographic scans were graded and correlated with abnormal cardiac variables. RESULTS: Peak levels of cTnT were elevated at 0.035 to 1.2 µg/L (mean ± SD, 0.27±0.38 µg/L) in 10 (20%) of 49 patients and were not associated with changes in creatine kinase MB fraction or ECG results. The cTnT levels did not correlate with location or side of hemorrhage or mortality at 30 days. Seventy (64%) of 110 patients displayed ECG abnormalities. The ECG changes did not correlate with the location or side of ICH, hydrocephalus, midline shift, or extension to the ventricles. CONCLUSION: The cTnT elevations in survivors of acute ICH are frequent but without confirmatory ECG changes that suggest mild myocardial injury. One-month mortality is not influenced by such cTnT elevations. In addition, ECG abnormalities are common but likely benign in patients with supratentorial ICH who survive the initial insult.
Mayo Clin Proc. 2006;81(2):192-196 cTnI = cardiac troponin I; cTnT = cardiac troponin T; ECG = electrocardiograpic; ICH = intracerebral hemorrhage; NICU = neurologic intensive care unit; SAH = subarachnoid hemorrhage
C
ardiac troponin T (cTnT) and cardiac troponin I (cTnI) are currently the tests of choice for detection of myocardial injury.1 The presence of elevated values of cardiac troponins in patients with acute neurologic diseases has been associated with an adverse prognosis. In a study of a heterogeneous group of patients with strokes, head injuries, and seizures, elevations in cTnI levels were observed in 19% of patients and correlated with poor prognosis.2 If this is also the case with intracerebral hemorrhage (ICH), then criteria for continued neurologic intensive care unit (NICU) observation should include elevated troponin values and cardiac arrhythmias. Several studies have examined the incidence and importance of cardiac troponins, cardiac arrhythmias, and electrocardiographic (ECG) changes in ischemic stroke and subarachnoid hemorrhage (SAH),3-7 but data in patients with ICHs are insufficient. 192
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We sought to define the incidence of these abnormalities and the importance of these findings to early mortality in a homogeneous group of patients with spontaneous ICHs. PATIENTS AND METHODS Data from patients with supratentorial ICH admitted to the Saint Marys Hospital NICU, Mayo Clinic, Rochester, Minn, from March 1998 to October 2003 were reviewed. We included patients with lobar, thalamic, and capsuloganglionic bleeds. The level of consciousness was graded on admission using the Glasgow Coma Scale. All patients underwent continuous ECG monitoring, blood pressure recording, and oxygen saturation monitoring. Rhythm disturbances recorded on paper strips were available later for review. A standard 12-lead ECG was performed at admission; additional ECGs were obtained if there were abnormalities in rhythm or morphology. Cardiologists interpreted all ECGs. We excluded moribund patients from the study, defined as those who died within 12 hours of admission, because comprehensive data were not available for these patients. Other exclusionary criteria were ICH secondary to trauma, primary or secondary tumors, vascular malformations, thrombolytic agents, and drug abuse. One patient with clinical myocardial infarction was excluded from the analysis. Agonal or terminal ECG patterns were also excluded from ECG analyses. Electrocardiographic findings and data from patients with prior ischemic heart disease or those taking cardioactive drugs such as β-blockers, calcium channel blockers, and inotropics were analyzed separately. A history of diabetes mellitus, hypertension, tobacco use, alcohol use, pulmonary disease, ischemic heart disease, renal failure, and seizures and prior medications were recorded for all patients. Cardiac troponin T levels were From the Department of Neurology and Division of Critical Care Neurology (B.V.M., E.M.M., J.R.F., E.F.M.W.) and Division of Cardiovascular Diseases (A.S.J.), Mayo Clinic College of Medicine, Rochester, Minn. Dr Maramattom is now with Lourdes Hospital, Vaduthala, Kochi, Kerala, India. Individual reprints of this article are not available. Address correspondence to Eelco F. M. Wijdicks, MD, Department of Neurology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). © 2006 Mayo Foundation for Medical Education and Research
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TROPONIN AND CARDIAC ABNORMALITIES IN ICH PATIENTS
tained using the JMP statistical software, version 5.0.1.2 (SAS Institute Inc, Cary, NC). Log rank tests were used for comparison of survival curves.
TABLE 1. Demographics and Clinical Characteristics of 75 Patients With ICH and Measured cTnT Values* No. (%) of patients
Sex
Male Female Medical history Diabetes Hypertension Prior cardiac illness Level of consciousness GCS score 3-7 GCS score 8-15 Location Lobar Frontal Temporal Parietal Occipital Extensive Ganglionic Thalamic Internal capsule Right Left CT location Subarachnoid extension of ICH Intraventricular extension of ICH Hydrocephalus Midline shift Outcome Dead
Group 1 (cTnT ≤0.035 µg/L) (n=39)
Group 2 (cTnT >0.035 µg/L) (n=10)
20 (51) 19 (49)
4 (40) 6 (60)
7 (18) 28 (72) 10 (26)
3 (30) 7 (70) 5 (50)
14 (36) 25 (64)
5 (50) 5 (50)
P value
RESULTS
.75
PATIENT CHARACTERISTICS There were 122 patients with supratentorial ICHs. Twelve moribund patients with primary ICH were excluded from the study because of incomplete data, leaving a study population of 110 patients. Patients ranged in age from 20 to 92 years (mean age, 71 years), and 55% were male. The location of the ICH was lobar in 60 patients, ganglionic in 30, thalamic in 17, internal capsule in 2, and bilateral in 1 patient. Right-sided ICH occurred in 65 patients (59%) and left-sided ICH in 45 patients (41%). Intraventricular extension of ICH was seen in 50 patients, and subarachnoid extension was found in 22 patients. Twenty-six patients underwent cTnI assays before August 2000, the results of which were normal in all patients. Fifty patients underwent the cTnT assay. In 30 patients, follow-up cTnT values were available. These patients were subdivided into 2 groups: group 1 had values of 0.035 µg/mL or less (39 patients), and group 2 had levels greater than 0.035 µg/mL (11 patients) (Table 1). Figure 1 details the final sample size.
.22 .11 .25 .47 .22
19 (49) 5 (13) 3 (8) 3 (8) 0 (0) 8 (21) 11 (28) 8 (21) 1 (2) 21 (54) 18 (46)
8 (80) 3 (30) 3 (30) 0 (0) 1 (10) 1 (10) 2 (20) 0 (0) 0 (0) 7 (70) 3 (30)
.15 .95 .49 .49 .20 .40 .46 .13 .79 .48 .29
11 (28)
3 (30)
.78
23 (59) 12 (31) 13 (33)
5 (50) 2 (20) 6 (60)
.72 .89 .16
16 (41)
2 (20)
.25
CARDIAC TROPONIN T Admission cTnT levels were elevated in 10 (20%) of 49 patients (95% confidence interval, 10-32). Elevations were modest (range, 0.035-1.2 µg/L; mean ± SD, 0.27±0.38 µg/L).
*The mean age of the patients was 73 years in group 1 and 63 years in group 2. CT = computed tomography; cTnT = cardiac troponin T; GCS = Glasgow Coma Scale; ICH = intracer ebral hemorrhage.
110 Study patients
determined on admission and on day 2 with a third-generation enzyme-linked immunosorbent assay (Roche, Basel, Switzerland). The 99th percentile with that assay and the 10% coefficient of variation are less than 0.01 µg/L and 0.035 µg/L, respectively.8 Before August 2000, assays were performed for cTnI (upper reference range of which was 0.5 ng/mL). Computed tomography was performed on admission or if there was any change in clinical status. Location of ICH, volume, subarachnoid or intraventricular presence of blood, hydrocephalus, and midline shift were noted. Midline shift was measured in millimeters at the level of the pineal gland and the septum pellucidum. Follow-up records were reviewed, and both 30- and 60-day mortality were recorded. Continuous variables were compared by unpaired t tests. Two or more categorical variables were analyzed by the χ2 test and Fisher exact test. All statistical analyses, including Kaplan-Meier survivor analysis curves, were obMayo Clin Proc.
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76 Troponin assay
26 cTnI assay normal levels
34 No troponin assay
50 cTnT assay
39 Group 1 10 Group 2 normal levels abnormal levels
1 Clinical MI*
FIGURE 1. Sample size depiction of patients undergoing analysis for troponin elevation. cTnI = cardiac troponin I; cTnT = cardiac troponin T; MI = myocardial infarction. *Patient excluded from analysis.
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TROPONIN AND CARDIAC ABNORMALITIES IN ICH PATIENTS
dysfunction. No correlation of cTnT was seen with location (Table 1), volume, and side of hemorrhage (P=.48), hydrocephalus (P=.89), extraparenchymal extension (P=.15), or midline shift (P=.16). The cTnT elevations remained common in patients with and without preexisting cardiac illness or other cardiovascular risk factors. Only 2 deaths occurred in this group in the first 60 days compared with 16 deaths in group 1. Sixty-day survival curves showed no difference between the 2 groups (P=.47) (Figure 2).
1.0
Survival
0.8 0.6 0.4
Group 1 (cTnT levels ≤0.035 µg/L) Group 2 (cTnT levels >0.035 µg/L)
0.2 0.0 0
5
10
15
20
25
30
Time to death (d)
FIGURE 2. Kaplan-Meier 60-day survival curves show no significant differences in survival between the 2 groups (P=.47).
These patients did not have a concomitant creatine kinase MB fraction elevation. One additional patient had a myocardial infarction diagnosed clinically with ECG changes of infarction. The cTnT level in this patient was 2.32 µg/L. This patient was excluded from the final analysis. Additional measurements of cTnT were available in 6 patients on day 2. This group also was not different clinically from the overall group. Twenty-four patients from group 2 also did not show further increases. The cTnT elevation was not associated with new-onset ECG changes on ECGs obtained either at admission or at 24 hours (P=.32). Patients without cTnT elevation showed similar ECG changes. Echocardiograms were performed in 6 patients with troponin elevations and showed no regional wall motion abnormalities or left ventricular TABLE 2. Types of ECG Changes in 110 Patients With Intracerebral Hemorrhage* ECG changes
No. (%) of patients
Sinus bradycardia Sinus tachycardia PSVC PVC SVT Atrial fibrillation or flutter Ectopic atrial rhythms, MAT, or PAT Junctional tachycardia QTc prolongation First-degree heart block RBBB ST-T morphologic changes LAFB Total
11 (10) 5 (4) 7 (6) 12 (11) 1 (1) 13 (12) 6 (5) 1 (1) 8 (7) 14 (13) 8 (7) 15 (14) 5 (4) 70 (64)
*ECG = electrocardiographic; LAFB = left anterior fascicular block; MAT = multifocal atrial tachycardia; PAT = paroxysmal atrial tachycardia; PSVC = premature supraventricular complexes; PVC = premature ventricular complex; QTc = corrected QT interval; RBBB = right bundle branch block; SVT = supraventricular tachycardia.
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ECG CHANGES All 110 patients had ECG recordings available for review. Changes in ECGs were seen in 70 patients (64%) (95% confidence interval, 54-72). Rhythm abnormalities were commonly seen (69%), even when patients with prior heart disease or previously documented ECG abnormalities were excluded. The common rhythm abnormalities were episodic sinus bradycardia, ventricular premature contractions, atrial fibrillation, and first-degree heart block (Table 2). Changes in ECGs were seen in 60 patients in the first 4 days and in 10 patients after 4 days. No life-threatening arrhythmias or ECG changes were seen during monitoring in the NICU. Major arrhythmias were defined as those requiring medical intervention or causing hemodynamic compromise. Major arrhythmias that required medical intervention occurred only in 1 patient and comprised a supraventricular tachycardia. ST-T planar segment changes that resembled ischemia were seen in 3 patients without concomitant cardiac marker changes and returned to normal on follow-up. All major ECG changes occurred only in right-sided ICH (P=.50). Mortality was not related to ECG changes (P=.27) (Table 3). After using unpaired t tests to compare proportions between groups with normal and elevated cTnT levels, ECG changes were not found to be correlated with elevated cTnT levels (P=.22) (Table 3). DISCUSSION Both cTnT and cTnI are currently considered the gold standard for detection of myocardial injury. The European Society of Cardiology and American College of Cardiology guidelines have suggested that levels above the 99th percentile be considered abnormal if they can be measured with 10% coefficient of variation. When these criteria are not met, it is suggested that the lowest value with a 10% coefficient of variation be used.8 This value is 0.035 µg/L for cTnT.8 Data on cTnT levels are not available in patients with ICH. In our homogeneous group of patients, modest elevations of cTnT levels (0.035-1.2 µg/L) were observed, but short-term prognosis did not appear to be influenced.
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TROPONIN AND CARDIAC ABNORMALITIES IN ICH PATIENTS
However, we only measured troponin levels in patients for 2 days and had only 30-day follow-up. Nevertheless, our data provide guidance for the clinical management of such patients during the acute phase of their illness. The most recent studies of patients with SAH have shown elevations of cardiac troponin levels in 17% to 28% of patients associated with left ventricular dysfunction clinically and on echocardiography.9-11 Some studies have shown an absence of a relationship between elevations of troponin levels and the clinical grade or amount of blood in patients,9,10 although other studies have established a close relationship between severe grades of SAH and cTnI elevation.11 It is thought that in addition to occult coronary artery disease, catecholamines may also mediate myocardial injury in patients with SAH. Increased intracranial pressure leads to marked release of catecholamines, which can induce tachycardia, coronary vasospasm, coronary and peripheral vasoconstriction, and direct myocardial toxicity due to increased intracellular calcium. In patients with stroke of varied origin, troponin elevations occurred in roughly 17% and were associated with an adverse prognosis over time.12 It is not surprising that our results clash with prior studies on SAH and stroke. There are some reasons for this discrepancy. First, series including patients with ischemic stroke12 have included those with a high frequency of cardioembolism (15%-20%) and ischemic heart disease, thus increasing the likelihood of troponin elevation and mortality. Second, elevated troponin levels and cutoff values were defined only in 2002.8 The major studies on the importance of troponin levels9,11,12 were conducted before this definition and used different cutoff values for cTnI or cTnT. Thus, we used well-defined cutoff levels for cTnT that were lower than those used in the literature, picking up even minor degrees of cardiac injury. However, we still could not discern a relationship between elevated cTnT levels and any of the neurologic variables such as location, side of hemorrhage, extraparenchymal extension, hydrocephalus, or midline shift. Third, we studied a homogeneous population in contrast to studies of patients with ischemic stroke. Moreover, our series cannot be compared with patients with SAHs who tend to have higher catecholamine surges and thus are likely to have higher troponin levels. Nevertheless, because of the nature of our study and exclusion of moribund patients, we may have excluded a group that likely would have shown cTnT elevations in the acute phase and assisted in establishing the relationship to mortality. Recent studies have shown elevation of cTnT levels in noncardiac conditions, such as pulmonary embolism, lobar pneumonia, acute heart failure, and end-stage renal disease.8,13-15 One could argue that we inadvertently Mayo Clin Proc.
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TABLE 3. Comparison of ECG Data and Mortality in Patients With or Without Increased Levels of cTnT* No. (%) of patients
ECG variable Atrial fibrillation RBBB ST-T planar changes Prolonged QT PVC Sinus tachycardia Mortality
Group 1 (cTnT ≤0.035 µg/L) (n=39)
Group 2 (cTnT >0.035 µg/L) (n=10)
P value
3 (8) 3 (8)
0 2 (20)
.54 .21
7 (18) 5 (13) 5 (13)
2 (20) 0 2 (20)
.52 .35 .36
2 (5) 16 (50)
2 (20) 2 (20)
.36 .27
*The total number of ECG changes was 32 in group 1 and 7 in group 2 (P=.32). cTnT = cardiac troponin T; ECG = electrocardiographic; PVC = premature ventricular complex; RBBB = right bundle branch block.
included patients with such conditions, which manifest prognostic importance. However, although end-stage renal disease may predispose to elevations in troponin levels, in our study only 2 such patients among the group had elevated troponin values. We believe that pragmatically clinicians would be more interested in the importance of troponin levels of patients who are likely to survive the first 24 hours of an ICH because the moribund group would have a poor prognosis. The results of our ECG and rhythm analysis are similar to those observed with troponin. It is well known that cardiac arrhythmias occur in cerebrovascular accidents, primarily ischemic strokes, and SAHs due to alterations in autonomic tone.1,2,4-7 Subarachnoid hemorrhage in particular induces a wide variety of ECG changes, such as QT prolongation, changes of ischemia, and life-threatening arrhythmias such as ventricular fibrillation or flutter and occasionally torsade de pointes.16-18 Two mechanisms are postulated: autonomic neural stimulation from the hypothalamus and elevated circulating catecholamines.6 Ischemic stroke also induces a wide array of cardiac arrhythmias. Right hemispheric strokes are more arrhythmogenic than are left-sided ones,1 and involvement of the insular cortex (frequently involved in middle cerebral artery stroke) predisposes patients to sudden cardiac death. Other locations implicated in the genesis of ECG changes include parts of the central autonomic network such as the amygdala and lateral hypothalamus. Heart rate variability, which has a circadian rhythm, may be reversibly abolished in the acute phase of ischemic stroke, further predisposing patients to arrhythmias and cardiac death.2,7 The literature that pertains to ECG abnormalities in patients with ICHs is limited, with only a few articles and small numbers of patients.19-22 Intracerebral hematomas can induce repolarization abnormalities, QT prolongation, neu-
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TROPONIN AND CARDIAC ABNORMALITIES IN ICH PATIENTS
rogenic T waves, and supraventricular arrhythmias. The incidence of ECG abnormalities has been found to be as high as 92.3%. Right hemispheric hematomas have been associated with supraventricular arrhythmias, specifically atrial extrasystoles, in small numbers of patients. Sudden cardiac death has also been seen, with a possible relationship to left hemispheric hematomas.10 Noncardiogenic pulmonary edema and spontaneous atrial fibrillation have been reported with brainstem hematomas.11 The proposed mechanism of ECG abnormalities is thought to be alterations in autonomic tone mediated by fibers projecting to the heart via the stellate ganglia. We found ECG abnormalities to be common in patients with ICHs (64%). However, most abnormalities were minor arrhythmias or morphologic changes, which did not require medical intervention and did not seem to be associated with increased mortality. Contrary to other studies, we did not find any correlation between hemorrhage localization and ECG changes. We found ECG changes suggestive of myocardial ischemia without concomitant troponin elevations, analogous to the changes in SAH suggestive of alterations in autonomic tone. In agreement with many recent studies of SAH, we found a lack of contribution of ECG changes to mortality.23,24 In our group of patients, the lack of life-threatening ECG changes could be attributed to the exclusion of moribund patients and the relatively low prevalence of coma (70% of our patients had a Glasgow Coma Scale score >8). Patients with sinus tachycardia or bundle branch block tended to manifest elevated cTnT levels, but, because of the small sample size, these interactions were not statistically significant. CONCLUSION We conclude that patients with supratentorial ICH may manifest mild or modest elevations of cTnT levels. This represents subclinical myocardial injury due to acute ICH when clinical or ECG manifestations of myocardial ischemia or left ventricular dysfunction are absent. Such elevations of cTnT levels do not influence the early outcome of patients. Prolonged observation in the NICU is not warranted. REFERENCES 1. Adams JE III, Bodor GS, Davila-Roman VG, et al. Cardiac troponin I: a marker with high specificity for cardiac injury. Circulation. 1993;88:101-106. 2. Dixit S, Castle M, Velu RP, Swisher L, Hodge C, Jaffe AS. Cardiac involvement in patients with acute neurologic disease: confirmation with cardiac troponin I. Arch Intern Med. 2000;160:3153-3158.
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3. Tokgözoglu SL, Batur MK, Topçuoglu MA, Saribas O, Kes S, Oto A. Effects of stroke localization on cardiac autonomic balance and sudden death. Stroke. 1999;30:1307-1311. 4. Korpelainen JT, Sotaniemi KA, Huikuri HV, Myllyla VV. Circadian rhythm of heart rate variability is reversibly abolished in ischemic stroke. Stroke. 1997;28:2150-2154. 5. Naver HK, Blomstrand C, Wallin BG. Reduced heart rate variability after right-sided stroke. Stroke. 1996;27:247-251. 6. Masson C, Lehericy S, Cohen Solal A, Verstichel P, Masson M. Electrocardiographic anomalies in relation with infarction in the territory of the anterior choroid artery [in French]. Rev Neurol (Paris). 1995;151:670673. 7. Davis TP, Alexander J, Lesch M. Electrocardiographic changes associated with acute cerebrovascular disease: a clinical review. Prog Cardiovasc Dis. 1993;36:245-260. 8. Apple FS, Wu AH, Jaffe AS. European Society of Cardiology and American College of Cardiology guidelines for redefinition of myocardial infarction: how to use existing assays clinically and for clinical trials. Am Heart J. 2002;144:981-986. 9. Horowitz MB, Willet D, Keffer J. The use of cardiac troponin-I (cTnI) to determine the incidence of myocardial ischemia and injury in patients with aneurysmal and presumed aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien). 1998;140:87-93. 10. 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. 11. 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. 12. James P, Ellis CJ, Whitlock RM, McNeil AR, Henley J, Anderson NE. Relation between troponin T concentration and mortality in patients presenting with an acute stroke: observational study. BMJ. 2000;320:1502-1504. 13. Pruszczyk P, Bochowicz A, Torbicki A, et al. Cardiac troponin T monitoring identifies high-risk group of normotensive patients with acute pulmonary embolism. Chest. 2003;123:1947-1952. 14. Freda BJ, Tang WH, Van Lente F, Peacock WF, Francis GS. Cardiac troponins in renal insufficiency: review and clinical implications. J Am Coll Cardiol. 2002;40:2065-2071. 15. Weinberg I, Cukierman T, Chajek-Shaul T. Troponin T elevation in lobar lung disease. Postgrad Med J. 2002;78:244-245. 16. Fukui S, Katoh H, Tsuzuki N, et al. Multivariate analysis of risk factors for QT prolongation following subarachnoid hemorrhage. Crit Care. 2003;7: R7-R12. 17. Randell T, Tanskanen P, Scheinin M, Kytta J, Ohman J, Lindgren L. QT dispersion after subarachnoid hemorrhage. J Neurosurg Anesthesiol. 1999;11: 163-166. 18. Lanzino G, Kongable GL, Kassell NF. Electrocardiographic abnormalities after nontraumatic subarachnoid hemorrhage. J Neurosurg Anesthesiol. 1994;6:156-162. 19. Chao CL, Chen WJ, Wu CC, Lee YT. Torsade de pointes and T-wave alternans in a patient with brainstem hemorrhage. Int J Cardiol. 1995;51:199201. 20. Serrano-Castro V, Gil-Peralta A, Gonzalez-Marcos JR, Moreno-Rojas A, Pedrote A, Errazquin P. Cardiac disease in intracerebral hematomas [in Spanish]. Rev Neurol. 1998;26:800-803. 21. Yamour BJ, Sridharan MR, Rice JF, Flowers NC. Electrocardiographic changes in cerebrovascular hemorrhage. Am Heart J. 1980;99:294-300. 22. Arruda WO, de Lacerda Junior FS. Electrocardiographic findings in acute cerebrovascular hemorrhage: a prospective study of 70 patients. Arq Neuropsiquiatr. 1992;50:269-274. 23. Brouwers PJ, Wijdicks EF, Hasan D, et al. Serial electrocardiographic recording in aneurysmal subarachnoid hemorrhage. Stroke. 1989;20:11621167. 24. Zaroff JG, Rordorf GA, Newell JB, Ogilvy CS, Levinson JR. Cardiac outcome in patients with subarachnoid hemorrhage and electrocardiographic abnormalities. Neurosurgery. 1999;44:34-39.
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