RESULTS Among the 48 patients recruited 4 were excluded because of congestive heart failure (signs of pulmonary edema on Rx film of the chest and/or reduced ventricular function on echocardiography) and 3 because of early death from ischemic stroke. The cause of early death was brain herniation in two patients, and heart failure in the other. The mean age of the patients excluded was 84.5 years; two were women and two were man. The four excluded patients showed very high levels of NT-PBNP (> 400 pmol/L) as it is expected in patients with heart failure. The remaining 41patients underwent the complete protocol of the study. The mean age of the 41 patients was 78.3 years (range: 54-91). There were 26 men and 15 women. None of the patients included had history of congestive heart failure nor underwent thrombolysis. We neither saw patients with renal failure on the basis of plasmatic creatinine levels. In table 1 are reported the main baseline characteristics and risk factors. | Table 1 Main baseline characteristics and risk factors. N=41 |
The type of stroke was ischemic in 29 patients and hemorrhagic of hypertensive cause in 12. Among ischemic strokes 6 were cardioembolic, 7 were lacunar, and the remainder (16) were ischemic non-cardioembolic (11 atherosclerotic and 5 of undetermined cause). The location of stroke was the anterior circulation in 30 patients and the posterior circulation in 11. The hemorrhagic stroke location was as follows: basal ganglia in 8, lobar in 2, thalamic in one patient, and cerebellar in another one. On delayed CT 14 patients showed evidence of brain edema and 27 did not. The mean age for patients with edema was 80.29 years (SD: 4.16), and 77.3 (SD: 7.67) for those without edema (difference not significant). Among patients with edema 3 were female and 11 male. History of hypertension was positive in 5 patients (35.7%) who showed edema and in 16 (59.2%) of those without edema. The mean systolic/diastolic blood pressure at baseline for patients with edema was 166/80 mm Hg in comparison to 163/77 in those without edema. After 48 hours of stroke onset the blood pressure only elevated in 3 patients with edema (from 130/75 to 160/92; from 155/85 to 170/95; and from 165/90 to 188/100); in the remainder it was similar as at baseline. The mean NIHSS score on admission was 7.5 (SD: 6.18) and at discharge it was 5.94 (SD: 6.54). For patients with ischemic stroke the baseline NIHSS was 7.6 (SD: 5.4) and 7.3 (SD: 5.1) for those with hemorrhage. The mean NIHSS score for patients with edema was 11.77 (SD: 6.5) and for those without edema it was 5.5 (SD: 4.2), which was significant on t-test (p=0.007). The mean length of stay in hospital was 8.2 days (range: 3-30 days), and 5 patients died from stroke after having obtained the second blood sample for determinations of the proteins. The mean Rankin score at discharge was 2.14 (SD: 1.83) with 22 patients being independent. None of the patients included in the study had overt evidence of infection on admission on the basis of standard blood and urine tests, X-film of the chest and temperature controls. In table 2 are presented the values of CRP and NT-PBNP of three determinations for all of the patients of the study. These values were increased in the three determinations in comparison to those of healthy people with the highest peak in the second determination. In table 3 are reported separately the same values for patients with edema and for those without edema. The 4 patients excluded because of congestive heart failure had very high levels of NT-PBNP (>400 pmol/l) and normal CRP values on admission. | Table 2 Mean values of CRP and NT-PBNP of the 41 patients |
| Table 3 Values of CRP and NT-PBNP for patients with and without brain edema. IQ range means 25-75% interquartile range. |
On admission the mean value of CRP for patients with edema was 4.7 mg/dl in comparison to 0.78 for patients without edema (p=0.001on MW-U-test), see figure 1. The difference remained significant after controlling for hypertension, atrial fibrillation, hyperlipidemia, diabetes and history of stroke. CRP values remained elevated after 48 hours and at discharge with significant higher levels in patients with edema. The ROC curve of the initial CRP values was predictive of edema with an area under the curve of 0.8 (95% CI: 0.64-0.95), see figure 2. | FIGURE 1 Graphic showing the mean values of plasmatic C-reactive protein in three determinations. |
| FIGURE 2 ROC curve of the CRP baseline values. Area under the curve: 0.8 (95% CI: 0.64-0.95). |
As it was expected the patients with lacunar infarctions had lower CRP levels (mean: 0.22 mg/dl) than those with non-lacunar stroke. All but one patient had the CRP level below 1 mg/dl. We neither saw differences in the baseline levels of CRP between the cardioembolic and atherosclerotic strokes (2.2 and 1.93 mg/dL respectively). In a model of logistic regression only baseline CRP level and systolic blood pressure were related to edema significantly (see table 4). Variables such as age, sex, atrial fibrillation, history of hypertension, and diabetes were excluded from the equation by the model. | Table 4 Model of logistic regression. Dependent variable was brain edema. |
The NT-PBNP values were also elevated in the three determinations but the between-group differences were not significant. However after 48 hours the values of NT-PBNP increased significantly more in patients with edema ( 133.6 pmol/l) in comparison to those without edema ( 1.58 pmol/l); p=0.002 on t-test. See figure 3. | FIGURE 3 Graphic showing the mean values of NT-PBNP in three determinations. Vertical axis represents the values in pmol/l. |
In table 5 are presented the different values for ischemic and hemorrhagic stroke without significant differences. Ischemic strokes showed higher values of NT-PBNP and lower values of CRP than hemorrhagic strokes without statistical significance. | Table 5 CRP and NT-PBNP values for ischemic and hemorrhagic stroke. |
We did not find relationship between systolic blood pressure on admission and values of CRP and NT-PBNP. We neither found relationship between the baseline values of CRP and NT-PBNP and dependence at discharge or death. The mean baseline CRP level for independent patients at discharge (Rankin 0, 1, or 2) was 1.64 (SD: 4.4) in comparison to 2.78 (SD: 4.5) in those dependent (Rankin 3,4, or 5), which was not significant. The levels of NT-PBNP were neither related to age (r=0.23) or sex. Although women had higher mean baseline levels of NT-PBNP than men (117.75 pmol/L and 95.21 respectively), the difference was not statistically significant (p=.69). Figure 4 represents and example of ischemic stroke and hemorrhagic stroke on baseline and delayed CT with edema developing after 48 hours. | FIGURE 4A. Ischemic stroke presenting with left hemiparesis. Normal CT on admission. CRP level: 6.9 m/dL; NT-PBNP level: 21pmol/L. B. CT scan after 48hours. Large infarction in the MCA territory showing mass-effect. CRP level: 7.9 mg/dL; NT-PBNP level: 139 pmol/L. (more ...) |
|
References 1. Edema, BE. In: Fauci AS, et al, eds. Harrison's principles of Internal Medicine, 14th ed. McGraw-Hill: New York; 1998. pp. 210–214. 2. Strunk, A; Bhalla, V; Clopton, P. et al. Impact of the history of congestive heart failure on the utlity of B-Type natriuretic peptide in the emergency diagnosis of heart failure: results from the Breathing Not Properly Multinational Study. Am J Med. 2006;119:69e1–69e11. [PubMed]3. Kragelund, C; Gronning, B; Kober, L; Hildebrandt, P; Steffensen, R. N-terminal pro-B-Type Natriuretic Peptide and long-term mortality in stable coronary heart disease. N Engl J Med. 2005;352:666–675. [PubMed]4. Kistorp, C; Raymond, I; Pedersen, F; Gustafsson, F; Faber, J; Hildebrandt, P. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA. 2005;293:1609–1616. [PubMed]5. Berger, R; Huelsman, M; Strecker, K. et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation. 2002;105:2392–2397. [PubMed]6. Wang, TJ; Larson, MG; Levy, D. et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004;350:655–663. [PubMed]7. Campbell, DJ; Woodward, M; Chalmers, JP. et al. Prediction of heart failure by amino terminal-pro-B-type natriuretic peptide and C-reactive protein in subjects with cerebrovascular disease. Hypertension. 2005;45:69–74. [PubMed]8. Campbell, DJ; Woodward, M; Chalmers, JP. et al. Prediction of myocardial infarction by N-terminal-pro-B-type natriuretic peptide, C-reactive protein, and renin in subjects with cerebrovascular disease. Circulation. 2005;112:110–116. [PubMed]9. Campbell, DJ; Woodward, M; Chalmers, JP. et al. Soluble vascular cell adhesion molecule 1 and N-terminal pro-B-type natriuretic peptide in predicting ischemic stroke in patients with cerebrovascular disease. Arch Neurol. 2006;63:60–65. [PubMed]10. Rost, NS; Wolf, PA; Kase, CS. et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke. 2001;32:2575–2579. [PubMed]11. Estrada, V; Tellez, MJ; Moya, J; Fernandez-Durango, R; Egido, J; Fernández-Cruz, AF. High plasma levels of endothelin-1 and atrial natriuretic peptide in patients with acute ischemic stroke. Am J Hypertens. 1994;7:1085–1089. [PubMed]12. Sato, Y; Maruoka, H; Honda, Y; Hachiya, N; Oizumi, K. Plasma concentration of atrial natriuretic peptide in cardioembolic stroke with atrial fibrillation. Kurume Med J. 1995;42:71–77. [PubMed]13. Makikallio, AM; Makikallio, TH; Korpelainen, JT. et al. Natriuretic peptides and mortality after stroke. Stroke. 2005;36:1016–1020. [PubMed]14. Etgen, T; Baum, H; Sander, K; Sander, D. Cardiac troponins and N-terminal pro-brain natriuretic peptide in acute ischemic stroke do not relate to clinical prognosis. Stroke. 2005;36:270–275. [PubMed]15. Giannakoulas, G; Hatzitolios, A; Karvounis, H. et al. N-terminal pro-brain natriuretic peptide levels are elevated in patients with acute ischemic stroke. Angiology. 2005;56:723–730. [PubMed]16. Ladenvall, C; Jood, K; Blomstrand, C; Nilsson, S; Jern, C; Ladenvall, P. Serum C-reactive protein concentration and genotype in relation to ischemic stroke subtype. Stroke. 2006;37:2018–2023. [PubMed]17. Audeberg, HJ; Rott, MM; Eck, T; Haberl, RL. Systemic inflammatory response depends on initial stroke severity but is attenuated by successful thrombolysis. Stroke. 2004;35:2128–2133. [PubMed]18. Marquardt, L; Ruf, A; Mansmann, U; Winter, R; Buggle, F; Kallenberg, K; Grau, AJ. Inflammatory response after acute ischemic stroke. J Neurol Sci. 2005;236:65–71. [PubMed]19. Masotti, L; Ceccarelli, E; Forconi, S; Cappelli, R. Prognostic role of C-reactive protein in very old patients with acute ischemic stroke. J Intern Med. 2005;258:145–152. [PubMed]20. Rallidis, LS; Vikelis, M; Panagiotakos, DB. Inflammatory markers and in-hospital mortality in acute ischemic stroke. Atherosclerosis. 2005. 21. Kocer, A; Canbulat, C; Gozke, E; Ilhan, A. C-reactive protein is an indicator for fatal outcomes in first-time stroke patients. Med Sci Monit. 2005;11:CR540–544. [PubMed]22. Arevalo-Lorido, JC; Carretero-Gomez, J; Calvo-Romero, JM. et al. C-reactive protein in the acute phase of ischemic stroke. Med Clin (Barc). 2005;125:775–777. [PubMed]23. Paffen, E; DeMaat, MP. C-reactive protein in atherosclerosis: A causal factor? Cardiovasc Res. 2006;71:30–39. [PubMed]24. Yip, HK; Sun, CK; Chang, LT; Chen, MC; Liou, CW. Time course and prognostic value of plasma levels of N-terminal pro-brain natriuretic peptide in patients after ischemic stroke. Circ J. 2006;70:447–452. [PubMed]25. Jensen, JK; Mickley, H; Bak, S; Korsholm, L; Kristensen, SR. Serial measurements of N-terminal pro-brain natriuretic peptide alter acute ischemic stroke. Cerebrovasc Dis. 2006;22:439–444. [PubMed]26. Tomida, M; Muraki, M; Uemura, K; Yamasaki, K. Olasma concentrations of brain natriuretic peptide in patients with subarachnoid hemorrhage. Stroke. 1998;29:1584–1587. [PubMed]27. McGirt, MJ; Blessing, R; Nimjee, SM. et al. Correlation of serum brain natriuretic peptide with hyponatremia and delayed ischemic neurological deficits after subarachnoid hemorrhage. Neurosurgery. 2004;54:1369–1373. [PubMed]28. Fukui, S; Nawashiro, H; Otani, N. et al. Focal brain edema and natriuretic peptides in patients with subarachnoid hemorrhage. Acta Neurochir (Wien). 2003;86:489–491. 29. Doczi, TP; Joo, F; Balas, I. Atrial natriuretic peptide (ANP) attenuates brain edema accompanying experimental subarachnoid hemorrhage. Acta Neurochir (Wien). 1995;132:87–91. [PubMed]30. Rosenberg, GA; Estrada, EY. Atrial natriuretic peptide blocks hemorrhagic brain edema after 4-hour delay in rats. Stroke. 1995;26:874–877. [PubMed]31. Nogami, M; Shiga, J; Takatsu, A; Endo, N; Ishiyama, I. Immunohistochemistry of atrial natriuretic peptide in brain infarction. Histochem J. 2001;33:87–90. [PubMed] |