- Email: [email protected]
Plasma brain natriuretic peptide is elevated in the acute phase of intracerebral hemorrhage
Journal of Clinical Neuroscience 21 (2014) 221–224
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Plasma brain natriuretic peptide is elevated in the acute phase of intracerebral hemorrhage Kensaku Shibazaki ⇑, Kazumi Kimura, Kenichiro Sakai, Junya Aoki, Yuki Sakamoto Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan
a r t i c l e
i n f o
Article history: Received 11 May 2012 Accepted 23 February 2013
Keywords: Brain natriuretic peptide Hydrocephalus Intracerebral hemorrhage Intraventricular extension
a b s t r a c t Previous reports have shown that plasma brain natriuretic peptide (BNP) levels are increased in patients with subarachnoid hemorrhage and ischemic stroke. We examined BNP in patients with intracerebral hemorrhage (ICH). Between June 2006 and February 2010, we prospectively enrolled consecutive patients with acute ICH within 24 hours of onset. The plasma BNP level was measured twice, on admission and 4 weeks after onset or at discharge. We investigated whether plasma BNP was elevated in the acute phase of ICH and associated factors. The mean ± standard deviation (SD) plasma BNP level of all patients was 71.1 ± 104.1 pg/mL. The log BNP level positively correlated with the cardio–thoracic ratio (r = 0.240, p = 0.0001). Moreover, BNP was significantly associated with intraventricular extension (p = 0.0039) and hydrocephalus (p = 0.0046). The mean ± SD BNP level of patients with cerebellar hemorrhage was the highest (130.2 ± 152.0 pg/mL), followed by brainstem (84.5 ± 170.6 pg/mL), lobar (72.4 ± 148.1 pg/mL), thalamus (64.8 ± 72.1 pg/mL), and putamen (59.9 ± 62.6 pg/mL) hemorrhages. In 185 patients, BNP was measured in the subacute phase of ICH. The BNP level in the acute phase of ICH was significantly higher than that in the subacute phase of ICH (69.3 ± 108.1 versus 21.7 ± 23.5 pg/mL, p < 0.0001). In conclusion, plasma BNP appears to be elevated in the acute phase of ICH, particularly in those with cerebellar lesions. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
2. Patients and methods
Brain natriuretic peptide (BNP) is a cardiac neurohormone secreted from the ventricles in response to ventricular volume expansion and pressure overload.1 Previous studies have shown that the BNP level is related to cardiac function2,3 and it has been used as a biochemical marker for congestive heart failure.4 In addition, plasma BNP levels have also been shown to be elevated in the acute phase of subarachnoid hemorrhage5–7 and in acute ischemic stroke patients.8–17 However the relationship between plasma BNP and intracerebral hemorrhage (ICH) has not been fully examined. Hypertension is the main risk factor for ICH18 and induces an increased load on the cardiac ventricles. Thus, hypertension causes left ventricular hypertrophy19 and systolic or diastolic dysfunction.20,21 In addition, early elevation of blood pressure after ICH is well documented.22 Therefore, we suspected that the plasma BNP level may be elevated in patients with ICH because of the increased load on the cardiac ventricles seen in the acute phase of ICH. We investigated this hypothesis and the presence of associated factors.
We prospectively enrolled consecutive acute spontaneous ICH patients within 24 hours of onset who were admitted to our Stroke Center between June 2006 and February 2010. Patients with underlying aneurysm, vascular malformation, dissection, hemorrhagic transformation of ischemic stroke, traumatic ICH, or those who underwent emergency surgery were excluded. In addition, patients with atrial fibrillation, dialysis-dependent chronic renal failure, or a history of myocardial infarction or chronic pulmonary disease were excluded from the present study, because plasma BNP levels are increased in these patients.23 The plasma BNP level was measured on admission. The study was conducted in compliance with the Declaration of Helsinki with regard to investigations in human subjects. The ethics committee of Kawasaki Medical School Hospital approved the study protocol. A diagnosis of acute ICH was made by stroke neurologists, and confirmed by CT scans or MRI. The following factors were assessed: age, sex, prior ICH, vascular risk factors, left ventricular hypertrophy, creatinine, cardio–thoracic ratio (CTR) on chest radiograph, systolic and diastolic blood pressure on admission, National Institutes of Health Stroke Scale (NIHSS) score24 on admission, ICH location, ICH volume on admission, ICH volume enlargement, subarachnoid extension, intraventricular extension, hydrocephalus, ICH score, and in-hospital death.
⇑ Corresponding author. Tel.: +81 86 464 1111; fax: +81 86 464 1199. E-mail address: [email protected] (K. Shibazaki). 0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2013.02.035
222
K. Shibazaki et al. / Journal of Clinical Neuroscience 21 (2014) 221–224
We also evaluated the following vascular risk factors: hypertension (defined as the use of antihypertensive agents, systolic blood pressure P140 mmHg or diastolic blood pressure P90 mmHg before stroke onset or 2 weeks after stroke onset), diabetes mellitus (defined as the use of oral hypoglycemic agents or insulin, fasting blood glucose level P126 mg/dL, or a glycosylated hemoglobin level P6.4%), and hyperlipidemia (defined as the use of antihyperlipidemic agents or a serum cholesterol level P220 mg/dL). Electrocardiographic left ventricular hypertrophy was defined as SV1 + RV5 or V6 P 3.5 mV.25 Cranial CT scanning was carried out twice, at the baseline visit (<24 hours after onset) and on follow-up (24–48 hours after onset). All cranial CT scans were performed according to our radiology department protocol, with an image matrix of 340 340 and a slice width of 8–10 mm. The investigators who read the CT scans had no prior knowledge of the clinical data. ICH volume was measured using the A B C/2 method, as described previously.26 The site of the ICH was classified according to the location of the largest amount of hematoma, and categorized as the putamen, thalamus, lobar, brainstem, or cerebellum.27 ICH enlargement was defined as a hematoma that grew by more than 33% of its initial volume.28 The ICH score is a clinical grading scale that is composed of five components related to outcome after nontraumatic ICH: the Glasgow Coma Scale score, ICH volume, presence of intraventricular hemorrhage, infratentorial origin, and age.29 All patients had baseline blood samples drawn on admission. Serum creatinine and plasma BNP were assessed. 2.1. Measurement of plasma BNP levels The plasma BNP level was measured twice, on admission and 4 weeks after ICH onset or at discharge. Samples were collected from a peripheral vein into tubes containing aprotinin and ethylene diamine tetra acetic acid (EDTA), and the plasma was isolated and then stored at 80 °C until analysis. The plasma BNP concentration was measured using a chemiluminescence enzyme immunoassay for human BNP (Shionogi & Co., Osaka, Japan). Briefly, this assay uses two monoclonal antibodies against human BNP, one recognizing a carboxyl-terminal sequence and the other the ring structure of BNP, and measures BNP by sandwiching it between the two antibodies. At our hospital the normal value of BNP is 618.4 pg/mL. The minimum detectable quantity of BNP is 3.9 pg/ mL. Investigators were blinded to the BNP results, and evaluated the clinical and radiographic findings.
56 patients were excluded because the plasma BNP level was increased due to atrial fibrillation (n = 23), dialysis-dependent chronic renal failure (n = 23), a history of myocardial infarction (n = 9), or a history of chronic pulmonary disease (n = 1). Therefore, 250 patients (164 men; 68.5 ± 12.8 years) were enrolled in the present study. The NIHSS score on admission was 13.3 ± 8.5. The location of the hematoma was the putamen in 78 patients (31%), thalamus in 96 (38%), lobar in 29 (12%), in the brainstem in 29 (12%), and in the cerebellum in 18 (7%). The interval of time from ICH onset to initial CT scan examination was 5.0 ± 4.9 hours. The ICH volume was 19.9 ± 33.6 mL. A total of 29 patients (11.6%) died during hospitalization. The interval from ICH onset to blood sample collection on admission was 4.1 ± 4.0 hours. The plasma BNP level of all patients was 71.1 ± 104.1 pg/mL. The log BNP level was positively correlated with age (r = 0.365, p < 0.0001), creatinine (r = 0.179, p = 0.0046), CTR (r = 0.240, p = 0.0001) and ICH volume (r = 0.132, p = 0.0376). The plasma BNP level was significantly higher in patients with intraventricular extension than in patients without intraventricular extension (77.9 ± 79.4 versus 66.6 ± 117.8 pg/mL, p = 0.0039) and was significantly higher in patients with hydrocephalus than in those without hydrocephalus (113.5 ± 159.7 versus 62.6 ± 86.9 pg/mL, p = 0.0046). The plasma BNP level of deceased patients was significantly higher than that of surviving patients (99.9 ± 101.6 versus 67.4 ± 104.1 pg/mL, p = 0.0030). There were no differences in other variables such as NIHSS score on admission (r = 0.081, p = 0.2034), or ICH enlargement (p = 0.2114). The BNP level of patients with cerebellar hemorrhage was the highest (130.2 ± 152.0 pg/mL), followed by brainstem (84.5 ± 170.6 pg/mL), lobar (72.4 ± 148.1 pg/mL), thalamus (64.8 ± 72.1 pg/mL), and putamen (59.9 ± 62.6 pg/mL) hemorrhage (Fig. 1). The plasma BNP level of patients with cerebellar hemorrhage was significantly higher than that of patients with putamen (p = 0.0064), thalamus (p = 0.0098), and lobar hemorrhage (p = 0.0500). The differences in BNP level between brainstem and cerebellum hemorrhage did not reach statistical significance (p = 0.1204). Table 1 shows the clinical characteristics in each ICH location. Older age, higher CTR, higher ICH score and intraventricular extension were more frequent in patients with cerebellar hemorrhage than in those with other ICH locations.
pg/ml P=0.0064 P=0.0098 P=0.0500
The Mann–Whitney U test was used to examine factors associated with plasma BNP level on admission. Linear regression analysis was performed to assess factors related to log BNP. Because the plasma BNP level had skewed distributions, it was log-transformed to normalize its distributions for analysis. Furthermore, we compared the clinical characteristics, including BNP level, for each ICH location using a chi-squired test and Kruskal–Wallis test. We investigated the differences in plasma BNP level between admission and on day 28 or at discharge using the Wilcoxon signed rank test. Statistical analysis was performed using a commercially available software package (StatView, version 5; SAS Institute, Cary, NC, USA). Differences were considered statistically significant at the level of p < 0.05. Results are reported as mean ± standard deviation (SD) unless otherwise stated. 4. Results A total of 306 consecutive acute spontaneous ICH patients were admitted to our Stroke Center within 24 hours of onset. Of these,
BNP level
3. Statistical analysis
n=78
n=96
n=29
n=29
n=18
Fig. 1. Column graph showing mean plasma brain natriuretic peptide (BNP) levels and intracerebral hemorrhage (ICH) locations. The mean ± standard deviation BNP level of patients with cerebellar hemorrhage was the highest (130.2 ± 152.0 pg/mL), followed by brainstem (84.5 ± 170.6 pg/mL), lobar (72.4 ± 148.1 pg/mL), thalamus (64.8 ± 72.1 pg/mL), and putamen (59.9 ± 62.6 pg/mL) hemorrhage. The plasma BNP level of patients with cerebellar hemorrhage was significantly higher than that of patients with putamen (p = 0.0064), thalamus (p = 0.0098), and lobar hemorrhage (p = 0.0500) (adjusted for cardio–thoracic ratio and ICH score).
223
K. Shibazaki et al. / Journal of Clinical Neuroscience 21 (2014) 221–224 Table 1 Patient demographics and intracerebral hemorrhage characteristics by location
Age, years Male Prior ICH Hypertension Diabetes mellitus Hyperlipidemia Left ventricular hypertrophy Creatinine Cardio–thoracic ratio Systolic blood pressure, mmHg Diastolic blood pressure, mmHg NIHSS score ICH volume, mL ICH volume enlargement Subarachnoid extension Intraventricular extension Hydrocephalus ICH score In-hospital death
Putamen n = 78
Thalamus n = 96
Lober n = 29
Brainstem n = 29
Cerebellum n = 18
p value
66 (14) 49 (63) 4 (5) 57 (73) 11 (14) 11 (14) 21 (27) 0.67 (0.20) 54.6 (4.6) 179 (34) 98 (23) 14 (8) 33.7 (49.2) 7/70 (9) 12 (15) 17 (22) 13 (17) 1.1 (1.0) 14 (18)
71 (12) 63 (66) 5 (5) 68 (71) 14 (15) 19 (20) 20 (21) 0.69 (0.26) 55.1 (5.5) 183 (25) 102 (18) 13 (6) 9.9 (8.1) 6/95 (6) 8 (8) 60 (63) 13 (14) 1.2 (0.9) 3 (3)
70 (14) 15 (52) 9 (31) 14 (48) 7 (24) 9 (31) 3 (10) 0.68 (0.26) 52.3 (5.5) 154 (19) 87 (17) 11 (9) 35.0 (38.6) 1/27 (3) 13 (45) 5 (17) 3 (10) 1.2 (1.2) 3 (10)
60 (11) 23 (79) 2 (7) 20 (69) 7 (24) 4 (14) 8 (28) 0.72 (0.28) 55.0 (5.8) 171 (30) 95 (22) 18 (12) 4.7 (4.8) 5/27 (17) 1 (3) 7 (24) 8 (28) 2.1 (1.3) 5 (17)
74 (8) 14 (78) 2 (11) 15 (83) 3 (17) 2 (11) 3 (17) 0.68 (0.22) 56.7 (9.2) 169 (23) 94 (18) 11 (10) 13.7 (20.3) 2/16 (11) 3 (17) 9 (50) 5 (28 2.5 (1.5) 4 (22)
0.0002 0.1752 0.0003 0.0793 0.5615 0.2601 0.3670 0.8019 0.2466 0.0001 0.0050 0.0931 <0.0001 0.2768 0.0001 <0.0001 0.2345 0.0001 0.0128
Data are presented as number (%). ICH = intracerebral hemorrhage, NIHSS = National Institutes of Health Stroke Scale.
Follow-up BNP was measured at 25 ± 10 days after ICH onset. In 65 of the 250 patients, plasma BNP could not be measured in the subacute phase of stroke because of death (n = 29), transfer to another department (n = 5), and not being measured (n = 31). The plasma BNP level in the acute phase of ICH was significantly higher than that in the subacute phase of ICH (69.3 ± 108.1 versus 21.7 ± 23.5 pg/mL, p < 0.0001). The BNP level reduced during the subacute phase of ICH in each location of ICH (Fig. 2). There was no difference in BNP level among the different locations of ICH in the subacute phase.
pg/ml
5. Discussion We have demonstrated that plasma BNP is elevated in the acute phase of ICH and reduced in the subacute phase of ICH. Furthermore, plasma BNP is significantly associated with the presence of intraventricular extension and hydrocephalus. There are a few possible explanations for the increase in plasma BNP level in patients with ICH. First, a previous study assumed that BNP production may be induced by a lesion to the hypothalamus caused by SAH.30 Interestingly, the plasma BNP level was
pg/ml
Putamen
pg/ml
Thalamus p<0.0001
pg/ml
Lobar p<0.0001
p=0.0208
pg/ml
Brainstem
Cerebellum p=0.0002
p=0.0033
Fig. 2. Column graphs showing serial changes in plasma brain natriuretic peptide (BNP) level in each location of intracerebral hemorrhage (ICH). The plasma BNP level in the acute phase of ICH was significantly higher than that in the subacute phase of ICH.
224
K. Shibazaki et al. / Journal of Clinical Neuroscience 21 (2014) 221–224
significantly associated with the presence of intraventricular extension and hydrocephalus, and was high in patients with cerebellar or brainstem hemorrhage in the present study. Intraventricular extension or hydrocephalus due to infratentorial lesions might influence the hypothalamus and trigger BNP secretion. Further study is necessary to evaluate this hypothesis. Second, neuroendocrine changes, including of catecholamine levels, due to ICH introduce an increased load on the cardiac ventricles. Takotsubo-like cardiomyopathy is occasionally a complication of ICH.31 Third, patients with a high levels of BNP have already suffered cardiac dysfunction prior to ICH onset. Hypertension is the main risk factor for ICH,18 and induces hypertensive heart disease.19–21 Furthermore, marked elevation of blood pressure in the acute phase of ICH might induce the increased load on the cardiac ventricle. The present results demonstrate a relationship between the plasma BNP level and the CTR. Thus, the plasma BNP level, being a marker of cardiac dysfunction, would be elevated in ICH patients. Little is known regarding the association between plasma BNP and ICH. In a previous small study (n = 44), a comparison of BNP levels between ICH and essential hypertension patients did not show a statistically significant relationship.8 In contrast, another small study (n = 25) found that the plasma BNP levels of ICH patients with hypertension were significantly higher than that of normotensive controls (15.9 ± 13.6 versus 7.4 ± 3.7 pg/mL, p < 0.05).32 To our knowledge, there has been no previous large study of the relationship between plasma BNP and ICH. Intravenous glycerol reduces cerebral edema and intracranial pressure in the acute phase of ICH. However, glycerol induces an increased load on the cardiac ventricles in patients with cardiac dysfunction. If the plasma BNP level in ICH is high, the increased load on the cardiac ventricle should be considered and a diagnostic workup performed, and the volume of intravenous fluids, including glycerol, and urine volume should be carefully monitored to avoid heart failure. Therefore, we propose routine measurement of plasma BNP to evaluate the load on the cardiac ventricle in patients with ICH. This study has several limitations. First, we did not evaluate cardiac function. Further detailed investigation of cardiac function, such as ejection fraction, ventricular septal thickness, and posterior wall thickness should be performed in a similar study. Second, the number of patients with cerebellar hemorrhage was relatively small. Third, follow-up BNP measurement was not performed in all patients. In conclusion, plasma BNP appears to be elevated in the acute phase of ICH, possibly due to the increased load on the heart. Further investigation is required to clarify this issue.
5.
6.
7.
8.
9. 10.
11.
12. 13.
14.
15.
16.
17.
18. 19.
20.
21. 22.
23.
24. 25.
Conflicts of interest/disclosure 26.
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References
27.
28. 29.
1. Maeda K, Takayoshi T, Wada A, et al. Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction. Am Heart J 1998;135:825–32. 2. Yamamoto K, Burnett Jr JC, Jougasaki M, et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996;28:988–94. 3. McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of leftventricular systolic dysfunction. Lancet 1998;351:9–13. 4. Tsutamoto T, Wada A, Maeda K, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure:
30.
31. 32.
prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997;96: 509–16. Tomida M, Muraki M, Uemura K, et al. Plasma concentrations of brain natriuretic peptide in patients with subarachnoid hemorrhage. Stroke 1998;29:1584–7. 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;54:1369–74. Tung PP, Olmsted E, Kopelnik A, et al. Plasma B-type natriuretic peptide levels are associated with early cardiac dysfunction after subarachnoid hemorrhage. Stroke 2005;36:1567–71. Nakagawa K, Yamaguchi T, Seida M, et al. Plasma concentrations of brain natriuretic peptide in patients with acute ischemic stroke. Cerebrovasc Dis 2005;19:157–64. Makikallio AM, Makikallio TH, Korpelainen JT, et al. Natriuretic peptides and mortality after stroke. Stroke 2005;36:1016–20. Jensen JK, Mickley H, Bak S, et al. Serial measurements of N-terminal pro-brain natriuretic peptide after acute ischemic stroke. Cerebrovasc Dis 2006;22: 439–44. Di Angelantonio E, De Castro S, Toni D, et al. Determinants of plasma levels of brain natriuretic peptide after acute ischemic stroke or TIA. J Neurol Sci 2007;260:139–42. Montaner J, Perea-Gainza M, Delgado P, et al. Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke 2008;39:2280–7. Shibazaki K, Kimura K, Iguchi Y, et al. Plasma brain natriuretic peptide can be a biological marker to distinguish cardioembolic stroke from other stroke subtypes in acute ischemic stroke. Intern Med 2009;48:259–64. Shibazaki K, Kimura K, Okada Y, et al. Heart failure may be associated with the onset of ischemic stroke with atrial fibrillation: a brain natriuretic peptide study. J Neurol Sci 2009;281:55–7. Shibazaki K, Kimura K, Okada Y, et al. Plasma brain natriuretic peptide as an independent predictor of in-hospital mortality after acute ischemic stroke. Intern Med 2009;48:1601–6. Okada Y, Shibazaki K, Kimura K, et al. Brain natriuretic peptide as a predictor of delayed atrial fibrillation after ischaemic stroke and transient ischaemic attack. Eur J Neurol 2010;17:326–31. Kimura K, Shibazaki K, Iguchi Y, et al. The combination of elevated BNP and AF as a predictor of no early recanalization after IV-t-PA in acute ischemic stroke. J Neurol Sci 2010;290:37–40. Kannel WB, Wolf PA, McGee DL, et al. Systolic pressure, arterial rigidity, and risk of stroke. The Framingham study. JAMA 1981;245:1225–9. Koren MJ, Devereux RB, Casale PN, et al. Relation of left ventricular mass and gemetry to morbidity and mortality in uncomplicated essential hypertension. Ann Int Med 1991;114:345–52. Drazner MH, Reichek N. Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years. The cardiovascular health study. J Am Coll Cardiol 2004;43:2207–15. Chaudhry GM, Schainfeld RM. Diastolic dysfunction and hypertension. N Engl J Med 2001;344:1401–2. Fogelholm R, Avikainen S, Murros K. Prognostic value and determinants of firstday mean arterial pressure in spontaneous supratentorial intracerebral hemorrhage. Stroke 1997;28:1396–400. Buckley MG, Sethi D, Markandu ND, et al. Plasma concentrations and comparisons of brain natriuretic peptide and atrial natriuretic peptide in normal subjects, cardiac transplant recipients and patients with dialysisindependent or dialysis-dependent chronic renal failure. Clin Sci (Lond) 1992;83:437–44. Lyden P, Brott T, Tilley B, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA stroke study group. Stroke 1994;25:2220–6. Kannel WB, Gordon T, Castelli WP, et al. Electrocardiographic left ventricular hypertrophy and risk of coronary heart disease: the Framingham study. Ann Intern Med 1970;72:813–22. Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996;27:1304–5. Inagawa T, Ohbayashi N, Takechi A, et al. Primary intracerebral hemorrhage in Izumo city, Japan: incidence rates and outcome in relation to the site of hemorrhage. Neurosurgery 2003;53:1283–97. Brott T, Broderick J, Kothari R, et al. Early hemorrhagic growth in patients with intracerebral hemorrhage. Stroke 1997;28:1–5. Hemphill 3rd JC, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891–7. Wijdicks EF, Schievink WI, Burnett Jr JC. Natriuretic peptide system and endothelin in aneurysmal subarachnoid hemorrhage. J Neurosurg 1997;87:275–80. Rahimi AR, Katayama M, Mills J. Cerebral hemorrhage: precipitating event for a tako-tsubo-like cardiomyopathy? Clin Cardiol 2008;31:275–80. Masugata H, Senda S, Goda F, et al. Differences in left ventricular hypertrophy and dysfunction between patients with cerebral hemorrhage and those with cerebral infarction. Tohoku J Exp Med 2008;215:159–65.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Plasma brain natriuretic peptide is elevated in the acute phase of intracerebral hemorrhage Kensaku Shibazaki ⇑, Kazumi Kimura, Kenichiro Sakai, Junya Aoki, Yuki Sakamoto Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan
a r t i c l e
i n f o
Article history: Received 11 May 2012 Accepted 23 February 2013
Keywords: Brain natriuretic peptide Hydrocephalus Intracerebral hemorrhage Intraventricular extension
a b s t r a c t Previous reports have shown that plasma brain natriuretic peptide (BNP) levels are increased in patients with subarachnoid hemorrhage and ischemic stroke. We examined BNP in patients with intracerebral hemorrhage (ICH). Between June 2006 and February 2010, we prospectively enrolled consecutive patients with acute ICH within 24 hours of onset. The plasma BNP level was measured twice, on admission and 4 weeks after onset or at discharge. We investigated whether plasma BNP was elevated in the acute phase of ICH and associated factors. The mean ± standard deviation (SD) plasma BNP level of all patients was 71.1 ± 104.1 pg/mL. The log BNP level positively correlated with the cardio–thoracic ratio (r = 0.240, p = 0.0001). Moreover, BNP was significantly associated with intraventricular extension (p = 0.0039) and hydrocephalus (p = 0.0046). The mean ± SD BNP level of patients with cerebellar hemorrhage was the highest (130.2 ± 152.0 pg/mL), followed by brainstem (84.5 ± 170.6 pg/mL), lobar (72.4 ± 148.1 pg/mL), thalamus (64.8 ± 72.1 pg/mL), and putamen (59.9 ± 62.6 pg/mL) hemorrhages. In 185 patients, BNP was measured in the subacute phase of ICH. The BNP level in the acute phase of ICH was significantly higher than that in the subacute phase of ICH (69.3 ± 108.1 versus 21.7 ± 23.5 pg/mL, p < 0.0001). In conclusion, plasma BNP appears to be elevated in the acute phase of ICH, particularly in those with cerebellar lesions. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
2. Patients and methods
Brain natriuretic peptide (BNP) is a cardiac neurohormone secreted from the ventricles in response to ventricular volume expansion and pressure overload.1 Previous studies have shown that the BNP level is related to cardiac function2,3 and it has been used as a biochemical marker for congestive heart failure.4 In addition, plasma BNP levels have also been shown to be elevated in the acute phase of subarachnoid hemorrhage5–7 and in acute ischemic stroke patients.8–17 However the relationship between plasma BNP and intracerebral hemorrhage (ICH) has not been fully examined. Hypertension is the main risk factor for ICH18 and induces an increased load on the cardiac ventricles. Thus, hypertension causes left ventricular hypertrophy19 and systolic or diastolic dysfunction.20,21 In addition, early elevation of blood pressure after ICH is well documented.22 Therefore, we suspected that the plasma BNP level may be elevated in patients with ICH because of the increased load on the cardiac ventricles seen in the acute phase of ICH. We investigated this hypothesis and the presence of associated factors.
We prospectively enrolled consecutive acute spontaneous ICH patients within 24 hours of onset who were admitted to our Stroke Center between June 2006 and February 2010. Patients with underlying aneurysm, vascular malformation, dissection, hemorrhagic transformation of ischemic stroke, traumatic ICH, or those who underwent emergency surgery were excluded. In addition, patients with atrial fibrillation, dialysis-dependent chronic renal failure, or a history of myocardial infarction or chronic pulmonary disease were excluded from the present study, because plasma BNP levels are increased in these patients.23 The plasma BNP level was measured on admission. The study was conducted in compliance with the Declaration of Helsinki with regard to investigations in human subjects. The ethics committee of Kawasaki Medical School Hospital approved the study protocol. A diagnosis of acute ICH was made by stroke neurologists, and confirmed by CT scans or MRI. The following factors were assessed: age, sex, prior ICH, vascular risk factors, left ventricular hypertrophy, creatinine, cardio–thoracic ratio (CTR) on chest radiograph, systolic and diastolic blood pressure on admission, National Institutes of Health Stroke Scale (NIHSS) score24 on admission, ICH location, ICH volume on admission, ICH volume enlargement, subarachnoid extension, intraventricular extension, hydrocephalus, ICH score, and in-hospital death.
⇑ Corresponding author. Tel.: +81 86 464 1111; fax: +81 86 464 1199. E-mail address: [email protected] (K. Shibazaki). 0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2013.02.035
222
K. Shibazaki et al. / Journal of Clinical Neuroscience 21 (2014) 221–224
We also evaluated the following vascular risk factors: hypertension (defined as the use of antihypertensive agents, systolic blood pressure P140 mmHg or diastolic blood pressure P90 mmHg before stroke onset or 2 weeks after stroke onset), diabetes mellitus (defined as the use of oral hypoglycemic agents or insulin, fasting blood glucose level P126 mg/dL, or a glycosylated hemoglobin level P6.4%), and hyperlipidemia (defined as the use of antihyperlipidemic agents or a serum cholesterol level P220 mg/dL). Electrocardiographic left ventricular hypertrophy was defined as SV1 + RV5 or V6 P 3.5 mV.25 Cranial CT scanning was carried out twice, at the baseline visit (<24 hours after onset) and on follow-up (24–48 hours after onset). All cranial CT scans were performed according to our radiology department protocol, with an image matrix of 340 340 and a slice width of 8–10 mm. The investigators who read the CT scans had no prior knowledge of the clinical data. ICH volume was measured using the A B C/2 method, as described previously.26 The site of the ICH was classified according to the location of the largest amount of hematoma, and categorized as the putamen, thalamus, lobar, brainstem, or cerebellum.27 ICH enlargement was defined as a hematoma that grew by more than 33% of its initial volume.28 The ICH score is a clinical grading scale that is composed of five components related to outcome after nontraumatic ICH: the Glasgow Coma Scale score, ICH volume, presence of intraventricular hemorrhage, infratentorial origin, and age.29 All patients had baseline blood samples drawn on admission. Serum creatinine and plasma BNP were assessed. 2.1. Measurement of plasma BNP levels The plasma BNP level was measured twice, on admission and 4 weeks after ICH onset or at discharge. Samples were collected from a peripheral vein into tubes containing aprotinin and ethylene diamine tetra acetic acid (EDTA), and the plasma was isolated and then stored at 80 °C until analysis. The plasma BNP concentration was measured using a chemiluminescence enzyme immunoassay for human BNP (Shionogi & Co., Osaka, Japan). Briefly, this assay uses two monoclonal antibodies against human BNP, one recognizing a carboxyl-terminal sequence and the other the ring structure of BNP, and measures BNP by sandwiching it between the two antibodies. At our hospital the normal value of BNP is 618.4 pg/mL. The minimum detectable quantity of BNP is 3.9 pg/ mL. Investigators were blinded to the BNP results, and evaluated the clinical and radiographic findings.
56 patients were excluded because the plasma BNP level was increased due to atrial fibrillation (n = 23), dialysis-dependent chronic renal failure (n = 23), a history of myocardial infarction (n = 9), or a history of chronic pulmonary disease (n = 1). Therefore, 250 patients (164 men; 68.5 ± 12.8 years) were enrolled in the present study. The NIHSS score on admission was 13.3 ± 8.5. The location of the hematoma was the putamen in 78 patients (31%), thalamus in 96 (38%), lobar in 29 (12%), in the brainstem in 29 (12%), and in the cerebellum in 18 (7%). The interval of time from ICH onset to initial CT scan examination was 5.0 ± 4.9 hours. The ICH volume was 19.9 ± 33.6 mL. A total of 29 patients (11.6%) died during hospitalization. The interval from ICH onset to blood sample collection on admission was 4.1 ± 4.0 hours. The plasma BNP level of all patients was 71.1 ± 104.1 pg/mL. The log BNP level was positively correlated with age (r = 0.365, p < 0.0001), creatinine (r = 0.179, p = 0.0046), CTR (r = 0.240, p = 0.0001) and ICH volume (r = 0.132, p = 0.0376). The plasma BNP level was significantly higher in patients with intraventricular extension than in patients without intraventricular extension (77.9 ± 79.4 versus 66.6 ± 117.8 pg/mL, p = 0.0039) and was significantly higher in patients with hydrocephalus than in those without hydrocephalus (113.5 ± 159.7 versus 62.6 ± 86.9 pg/mL, p = 0.0046). The plasma BNP level of deceased patients was significantly higher than that of surviving patients (99.9 ± 101.6 versus 67.4 ± 104.1 pg/mL, p = 0.0030). There were no differences in other variables such as NIHSS score on admission (r = 0.081, p = 0.2034), or ICH enlargement (p = 0.2114). The BNP level of patients with cerebellar hemorrhage was the highest (130.2 ± 152.0 pg/mL), followed by brainstem (84.5 ± 170.6 pg/mL), lobar (72.4 ± 148.1 pg/mL), thalamus (64.8 ± 72.1 pg/mL), and putamen (59.9 ± 62.6 pg/mL) hemorrhage (Fig. 1). The plasma BNP level of patients with cerebellar hemorrhage was significantly higher than that of patients with putamen (p = 0.0064), thalamus (p = 0.0098), and lobar hemorrhage (p = 0.0500). The differences in BNP level between brainstem and cerebellum hemorrhage did not reach statistical significance (p = 0.1204). Table 1 shows the clinical characteristics in each ICH location. Older age, higher CTR, higher ICH score and intraventricular extension were more frequent in patients with cerebellar hemorrhage than in those with other ICH locations.
pg/ml P=0.0064 P=0.0098 P=0.0500
The Mann–Whitney U test was used to examine factors associated with plasma BNP level on admission. Linear regression analysis was performed to assess factors related to log BNP. Because the plasma BNP level had skewed distributions, it was log-transformed to normalize its distributions for analysis. Furthermore, we compared the clinical characteristics, including BNP level, for each ICH location using a chi-squired test and Kruskal–Wallis test. We investigated the differences in plasma BNP level between admission and on day 28 or at discharge using the Wilcoxon signed rank test. Statistical analysis was performed using a commercially available software package (StatView, version 5; SAS Institute, Cary, NC, USA). Differences were considered statistically significant at the level of p < 0.05. Results are reported as mean ± standard deviation (SD) unless otherwise stated. 4. Results A total of 306 consecutive acute spontaneous ICH patients were admitted to our Stroke Center within 24 hours of onset. Of these,
BNP level
3. Statistical analysis
n=78
n=96
n=29
n=29
n=18
Fig. 1. Column graph showing mean plasma brain natriuretic peptide (BNP) levels and intracerebral hemorrhage (ICH) locations. The mean ± standard deviation BNP level of patients with cerebellar hemorrhage was the highest (130.2 ± 152.0 pg/mL), followed by brainstem (84.5 ± 170.6 pg/mL), lobar (72.4 ± 148.1 pg/mL), thalamus (64.8 ± 72.1 pg/mL), and putamen (59.9 ± 62.6 pg/mL) hemorrhage. The plasma BNP level of patients with cerebellar hemorrhage was significantly higher than that of patients with putamen (p = 0.0064), thalamus (p = 0.0098), and lobar hemorrhage (p = 0.0500) (adjusted for cardio–thoracic ratio and ICH score).
223
K. Shibazaki et al. / Journal of Clinical Neuroscience 21 (2014) 221–224 Table 1 Patient demographics and intracerebral hemorrhage characteristics by location
Age, years Male Prior ICH Hypertension Diabetes mellitus Hyperlipidemia Left ventricular hypertrophy Creatinine Cardio–thoracic ratio Systolic blood pressure, mmHg Diastolic blood pressure, mmHg NIHSS score ICH volume, mL ICH volume enlargement Subarachnoid extension Intraventricular extension Hydrocephalus ICH score In-hospital death
Putamen n = 78
Thalamus n = 96
Lober n = 29
Brainstem n = 29
Cerebellum n = 18
p value
66 (14) 49 (63) 4 (5) 57 (73) 11 (14) 11 (14) 21 (27) 0.67 (0.20) 54.6 (4.6) 179 (34) 98 (23) 14 (8) 33.7 (49.2) 7/70 (9) 12 (15) 17 (22) 13 (17) 1.1 (1.0) 14 (18)
71 (12) 63 (66) 5 (5) 68 (71) 14 (15) 19 (20) 20 (21) 0.69 (0.26) 55.1 (5.5) 183 (25) 102 (18) 13 (6) 9.9 (8.1) 6/95 (6) 8 (8) 60 (63) 13 (14) 1.2 (0.9) 3 (3)
70 (14) 15 (52) 9 (31) 14 (48) 7 (24) 9 (31) 3 (10) 0.68 (0.26) 52.3 (5.5) 154 (19) 87 (17) 11 (9) 35.0 (38.6) 1/27 (3) 13 (45) 5 (17) 3 (10) 1.2 (1.2) 3 (10)
60 (11) 23 (79) 2 (7) 20 (69) 7 (24) 4 (14) 8 (28) 0.72 (0.28) 55.0 (5.8) 171 (30) 95 (22) 18 (12) 4.7 (4.8) 5/27 (17) 1 (3) 7 (24) 8 (28) 2.1 (1.3) 5 (17)
74 (8) 14 (78) 2 (11) 15 (83) 3 (17) 2 (11) 3 (17) 0.68 (0.22) 56.7 (9.2) 169 (23) 94 (18) 11 (10) 13.7 (20.3) 2/16 (11) 3 (17) 9 (50) 5 (28 2.5 (1.5) 4 (22)
0.0002 0.1752 0.0003 0.0793 0.5615 0.2601 0.3670 0.8019 0.2466 0.0001 0.0050 0.0931 <0.0001 0.2768 0.0001 <0.0001 0.2345 0.0001 0.0128
Data are presented as number (%). ICH = intracerebral hemorrhage, NIHSS = National Institutes of Health Stroke Scale.
Follow-up BNP was measured at 25 ± 10 days after ICH onset. In 65 of the 250 patients, plasma BNP could not be measured in the subacute phase of stroke because of death (n = 29), transfer to another department (n = 5), and not being measured (n = 31). The plasma BNP level in the acute phase of ICH was significantly higher than that in the subacute phase of ICH (69.3 ± 108.1 versus 21.7 ± 23.5 pg/mL, p < 0.0001). The BNP level reduced during the subacute phase of ICH in each location of ICH (Fig. 2). There was no difference in BNP level among the different locations of ICH in the subacute phase.
pg/ml
5. Discussion We have demonstrated that plasma BNP is elevated in the acute phase of ICH and reduced in the subacute phase of ICH. Furthermore, plasma BNP is significantly associated with the presence of intraventricular extension and hydrocephalus. There are a few possible explanations for the increase in plasma BNP level in patients with ICH. First, a previous study assumed that BNP production may be induced by a lesion to the hypothalamus caused by SAH.30 Interestingly, the plasma BNP level was
pg/ml
Putamen
pg/ml
Thalamus p<0.0001
pg/ml
Lobar p<0.0001
p=0.0208
pg/ml
Brainstem
Cerebellum p=0.0002
p=0.0033
Fig. 2. Column graphs showing serial changes in plasma brain natriuretic peptide (BNP) level in each location of intracerebral hemorrhage (ICH). The plasma BNP level in the acute phase of ICH was significantly higher than that in the subacute phase of ICH.
224
K. Shibazaki et al. / Journal of Clinical Neuroscience 21 (2014) 221–224
significantly associated with the presence of intraventricular extension and hydrocephalus, and was high in patients with cerebellar or brainstem hemorrhage in the present study. Intraventricular extension or hydrocephalus due to infratentorial lesions might influence the hypothalamus and trigger BNP secretion. Further study is necessary to evaluate this hypothesis. Second, neuroendocrine changes, including of catecholamine levels, due to ICH introduce an increased load on the cardiac ventricles. Takotsubo-like cardiomyopathy is occasionally a complication of ICH.31 Third, patients with a high levels of BNP have already suffered cardiac dysfunction prior to ICH onset. Hypertension is the main risk factor for ICH,18 and induces hypertensive heart disease.19–21 Furthermore, marked elevation of blood pressure in the acute phase of ICH might induce the increased load on the cardiac ventricle. The present results demonstrate a relationship between the plasma BNP level and the CTR. Thus, the plasma BNP level, being a marker of cardiac dysfunction, would be elevated in ICH patients. Little is known regarding the association between plasma BNP and ICH. In a previous small study (n = 44), a comparison of BNP levels between ICH and essential hypertension patients did not show a statistically significant relationship.8 In contrast, another small study (n = 25) found that the plasma BNP levels of ICH patients with hypertension were significantly higher than that of normotensive controls (15.9 ± 13.6 versus 7.4 ± 3.7 pg/mL, p < 0.05).32 To our knowledge, there has been no previous large study of the relationship between plasma BNP and ICH. Intravenous glycerol reduces cerebral edema and intracranial pressure in the acute phase of ICH. However, glycerol induces an increased load on the cardiac ventricles in patients with cardiac dysfunction. If the plasma BNP level in ICH is high, the increased load on the cardiac ventricle should be considered and a diagnostic workup performed, and the volume of intravenous fluids, including glycerol, and urine volume should be carefully monitored to avoid heart failure. Therefore, we propose routine measurement of plasma BNP to evaluate the load on the cardiac ventricle in patients with ICH. This study has several limitations. First, we did not evaluate cardiac function. Further detailed investigation of cardiac function, such as ejection fraction, ventricular septal thickness, and posterior wall thickness should be performed in a similar study. Second, the number of patients with cerebellar hemorrhage was relatively small. Third, follow-up BNP measurement was not performed in all patients. In conclusion, plasma BNP appears to be elevated in the acute phase of ICH, possibly due to the increased load on the heart. Further investigation is required to clarify this issue.
5.
6.
7.
8.
9. 10.
11.
12. 13.
14.
15.
16.
17.
18. 19.
20.
21. 22.
23.
24. 25.
Conflicts of interest/disclosure 26.
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References
27.
28. 29.
1. Maeda K, Takayoshi T, Wada A, et al. Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction. Am Heart J 1998;135:825–32. 2. Yamamoto K, Burnett Jr JC, Jougasaki M, et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996;28:988–94. 3. McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of leftventricular systolic dysfunction. Lancet 1998;351:9–13. 4. Tsutamoto T, Wada A, Maeda K, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure:
30.
31. 32.
prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997;96: 509–16. Tomida M, Muraki M, Uemura K, et al. Plasma concentrations of brain natriuretic peptide in patients with subarachnoid hemorrhage. Stroke 1998;29:1584–7. 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;54:1369–74. Tung PP, Olmsted E, Kopelnik A, et al. Plasma B-type natriuretic peptide levels are associated with early cardiac dysfunction after subarachnoid hemorrhage. Stroke 2005;36:1567–71. Nakagawa K, Yamaguchi T, Seida M, et al. Plasma concentrations of brain natriuretic peptide in patients with acute ischemic stroke. Cerebrovasc Dis 2005;19:157–64. Makikallio AM, Makikallio TH, Korpelainen JT, et al. Natriuretic peptides and mortality after stroke. Stroke 2005;36:1016–20. Jensen JK, Mickley H, Bak S, et al. Serial measurements of N-terminal pro-brain natriuretic peptide after acute ischemic stroke. Cerebrovasc Dis 2006;22: 439–44. Di Angelantonio E, De Castro S, Toni D, et al. Determinants of plasma levels of brain natriuretic peptide after acute ischemic stroke or TIA. J Neurol Sci 2007;260:139–42. Montaner J, Perea-Gainza M, Delgado P, et al. Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke 2008;39:2280–7. Shibazaki K, Kimura K, Iguchi Y, et al. Plasma brain natriuretic peptide can be a biological marker to distinguish cardioembolic stroke from other stroke subtypes in acute ischemic stroke. Intern Med 2009;48:259–64. Shibazaki K, Kimura K, Okada Y, et al. Heart failure may be associated with the onset of ischemic stroke with atrial fibrillation: a brain natriuretic peptide study. J Neurol Sci 2009;281:55–7. Shibazaki K, Kimura K, Okada Y, et al. Plasma brain natriuretic peptide as an independent predictor of in-hospital mortality after acute ischemic stroke. Intern Med 2009;48:1601–6. Okada Y, Shibazaki K, Kimura K, et al. Brain natriuretic peptide as a predictor of delayed atrial fibrillation after ischaemic stroke and transient ischaemic attack. Eur J Neurol 2010;17:326–31. Kimura K, Shibazaki K, Iguchi Y, et al. The combination of elevated BNP and AF as a predictor of no early recanalization after IV-t-PA in acute ischemic stroke. J Neurol Sci 2010;290:37–40. Kannel WB, Wolf PA, McGee DL, et al. Systolic pressure, arterial rigidity, and risk of stroke. The Framingham study. JAMA 1981;245:1225–9. Koren MJ, Devereux RB, Casale PN, et al. Relation of left ventricular mass and gemetry to morbidity and mortality in uncomplicated essential hypertension. Ann Int Med 1991;114:345–52. Drazner MH, Reichek N. Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years. The cardiovascular health study. J Am Coll Cardiol 2004;43:2207–15. Chaudhry GM, Schainfeld RM. Diastolic dysfunction and hypertension. N Engl J Med 2001;344:1401–2. Fogelholm R, Avikainen S, Murros K. Prognostic value and determinants of firstday mean arterial pressure in spontaneous supratentorial intracerebral hemorrhage. Stroke 1997;28:1396–400. Buckley MG, Sethi D, Markandu ND, et al. Plasma concentrations and comparisons of brain natriuretic peptide and atrial natriuretic peptide in normal subjects, cardiac transplant recipients and patients with dialysisindependent or dialysis-dependent chronic renal failure. Clin Sci (Lond) 1992;83:437–44. Lyden P, Brott T, Tilley B, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA stroke study group. Stroke 1994;25:2220–6. Kannel WB, Gordon T, Castelli WP, et al. Electrocardiographic left ventricular hypertrophy and risk of coronary heart disease: the Framingham study. Ann Intern Med 1970;72:813–22. Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996;27:1304–5. Inagawa T, Ohbayashi N, Takechi A, et al. Primary intracerebral hemorrhage in Izumo city, Japan: incidence rates and outcome in relation to the site of hemorrhage. Neurosurgery 2003;53:1283–97. Brott T, Broderick J, Kothari R, et al. Early hemorrhagic growth in patients with intracerebral hemorrhage. Stroke 1997;28:1–5. Hemphill 3rd JC, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891–7. Wijdicks EF, Schievink WI, Burnett Jr JC. Natriuretic peptide system and endothelin in aneurysmal subarachnoid hemorrhage. J Neurosurg 1997;87:275–80. Rahimi AR, Katayama M, Mills J. Cerebral hemorrhage: precipitating event for a tako-tsubo-like cardiomyopathy? Clin Cardiol 2008;31:275–80. Masugata H, Senda S, Goda F, et al. Differences in left ventricular hypertrophy and dysfunction between patients with cerebral hemorrhage and those with cerebral infarction. Tohoku J Exp Med 2008;215:159–65.