Preload in Patients with High Volume Load

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1 Tohoku J. Exp. Med., 2010, 221, Blood N-Terminal probnp as an Indicator of Cardiac Preload 175 Blood N-Terminal probnp as a Potential Indicator of Cardiac Preload in Patients with High Volume Load Satoshi Yamanouchi, 1 Daisuke Kudo, 1 Tomoyuki Endo, 1 Yuka Kitano 1 and Yotaro Shinozawa 1 1 Emergency Center, Tohoku University Hospital, Sendai, Japan Keywords: brain natriuretic peptide; NT-proBNP; cardiac index; global end-diastolic volume index Tohoku J. Exp. Med., 2010, 221 (3), Tohoku University Medical Press Brain natriuretic peptide (BNP) is the second member of the natriuretic peptide family (Sudoh et al. 1988), which was discovered after atrial natriuretic peptide (ANP). BNP was initially identified in the brain but is mainly produced and secreted by cardiomyocytes. Natriuretic peptides have various effects, such as a diuretic effect, a natriuretic activity, a hypotensive effect based on a vascular smooth muscle relaxant effect, and an anti-secretory action of aldosterone (Sudoh et al. 1988). Importantly, the main stimulus for synthesis and release of BNP is myocardial wall stretch (Kinnunen et al. 1993; Nakagawa et al. 1995). Furthermore, expression of the gene that encodes BNP can be induced rapidly after myocardial wall stretch, which also makes it a useful biomarker for acute situations (Pemberton et al. 2000). A previous study revealed a correlation between the blood BNP level and preload (Dastoor et al. 2005). BNP is synthesized as probnp and is cleaved to BNP and N-terminal probnp (NT-proBNP) within cardiomyocytes (Vanderheyden et al. 2004). BNP is cleared from blood through natriuretic peptide receptor type C and proteolysis by neutral endopeptidases (Weber and Hamm 2006). In contrast, NT-proBNP is mainly cleared by renal excretion. Due to the difference in the metabolic pathways, NTproBNP is known to have a longer half-life in blood compared to BNP (120 minutes vs. 22 minutes) and to show good stability in stored blood specimens (Varpula et al. 2007). Therefore, if the correlation between the blood NTproBNP and preload exists, the blood NT-proBNP level will become a better indicator of preload than the blood BNP level. Furthermore, availability of a commercial kit allows us to measure the blood NT-proBNP at the bedside within 15 min. In recent years, hemodynamic monitoring with transpulmonary thermodilution and arterial pulse contour analysis (measuring cardiac output, global end-diastolic volume, extravascular lung water, etc.) has frequently been used for keeping track of hemodynamic status in serious patients (Oren-Grinberg 2010). Global end-diastolic volume index (GEDVI) is known to be a reliable indicator of cardiac preload (Gödje et al.1998; Sakka et al. 1999). The present study was undertaken to examine a correlation between blood NT-proBNP levels and GEDVI and to investigate Received January 14, 2010; revision accepted for publication April 30, doi: /tjem Correspondence : Satoshi Yamanouchi, Emergency Center, Tohoku University Hospital, 1-1 Seiryo-cho, Aoba-ku, Sendai , Japan. y-3104@yc4.so-net.ne.jp 175

2 176 S. Yamanouchi et al. Table 1. Patient characteristics. Patient Age Gender Diseases & Injuries outcome 1 81 male Burn (36 % TBSA, Inhalation injury) alive 2 14 male Burn (42 % TBSA) alive 3 79 male Burn (7 % TBSA, Inhalation injury) alive 4 65 male Sepsis, pneumonia alive 5 59 male Sepsis, UTI alive 6 72 male Sepsis, UTI alive 7 67 male AKA dead 8 22 male Resuscitated patient alive AKA, alcoholic ketoacidosis; TBSA, total body surface area; UTI, urinary tract infection. whether NT-proBNP could be used as a potential indicator of cardiac preload. Subjects and Methods Subjects Of 233 patients hospitalized at the Tohoku University Hospital Emergency Center over five months (from May to September 2007), 8 wounded and sick patients who required the administration of large volume of intravenous fluids (greater than about 1,000 ml within 4 hours after hospitalization) were enrolled as subjects. All the subjects were male, with an average age of 57.6 ± 25.3 years old, and admitted for the following medical conditions: burn (3 subjects), sepsis (3 subjects), alcoholic ketoacidosis (1 subject) and a patient with cardiac arrest secondary to ventricular fibrillation who was successfully resuscitated (Table 1). The present study was performed based on the protocol approved by the Ethics Committee in Tohoku University School of Medicine. Methods For monitoring hemodynamics, we used PiCCO system (PULSION Medical Systems, Munich, Germany). PiCCO system is a transpulmonary thermodilution method, which can provide information on the volume status. PiCCO system measures GEDVI and extravascular lung water index (EVLWI), which can be used as indicators of cardiac preload and pulmonary edema, respectively. And PiCCO system measures cardiac index (CI) by two ways: the transpulmonary thermodilution method and the pulse contour analysis (Chaney and Derdak 2002; Oren-Grinberg 2010). A central venous catheter and a PiCCO arterial catheter were inserted into the internal jugular vein and the femoral artery, respectively, as soon as practicable after initial treatment. Then 15 ml of physiological saline solution at 0 to 4 C was injected into the internal jugular vein to provide various parameters (CI, GEDVI, EVLWI) through analysis of variations in the blood temperature taken by the temperature sensor of the arterial catheter and variations in the arterial pressure waveform. The volume for infusion was determined through comprehensive consideration of the vital signs, urinary volumes, and various hemodynamic parameters. The recording of various PiCCO values and blood sampling for NT-proBNP were carried out at least every 8 hours. We thus measured PiCCO values at 47 time points. NT-proBNP levels were measured by immunoassay with a Cardiac reader (Roche Diagnostics, Basel, Switzerland). Heparinized total blood was immediately tested at the bedside for the NT-proBNP (detection range: 60-3,000 pg/ml). The normal range was less than 125 pg/ml. As for the statistical software used, Stat View Ver. 5.0 (SAS Institute Inc., North Carolina, USA) was utilized, with the significance level defined as p < Results Variations in blood NT-proBNP over time Within 24 hours, subjects with sepsis (patients 4, 5 and 6) exhibited the marked increase in the blood NT-proBNP levels that were greater than the measurement limit of 3,000 pg/ml (Fig. 1). The small magnitude of the increase in the NT-proBNP levels was observed in one patient with burn (patient 2) and one patient (patient 8) that required fluid resuscitation after cardiopulmonary arrest. The overall average of blood NT-proBNP levels was 1,316.3 ± 1,154.5 pg/ml (47 samples from the eight patients). It should be noted, however, that the calculated average might be underestimated, because the values that were greater than the measurement limit of 3,000 pg/ml were included as 3,000 pg/ml. Correlations between NT-proBNP levels and various hemodynamic parameters Correlations between NT-proBNP levels and CI, GEDVI and EVLWI were examined in the range of NTproBNP levels less than 3,000 pg/ml (39 samples). There were positive correlations of NT-proBNP levels with CI (Fig. 2a; r = 0.68, p < ) and with GEDVI (Fig. 2b; r = 0.61, p < ). In contrast, there was no correlation between NT-proBNP levels and EVLWI (Fig. 2c). Correlation between GEDVI and CI among groups of blood NT-proBNP levels There was a positive correlation between GEDVI and CI (r = 0.80, p < ) except for the values that were greater than the measurement limit of 3,000 pg/ml for NTproBNP levels (Fig. 3). There were 39 measurement points. We divided these measurement points into 3 groups according to NT-proBNP levels. The cutoff value to rule out acute heart failure is below 300 pg/ml (Januzzi et al. 2006). The group of low NT-proBNP levels ( pg/ml) showed

3 Blood N-Terminal probnp as an Indicator of Cardiac Preload 177 Fig. 1. Time-dependent changes in blood NT-proBNP levels. Plotted are the values of 47 blood samples. Within 24 hours, subjects with sepsis (patients 4, 5 and 6) exhibited the marked increase in the blood NT-proBNP levels that were greater than the measurement limit of 3,000 pg/ml. The small magnitude of the increase in the NT-proBNP levels was observed in one patient with burn (patient 2) and one patient (patient 8) that required fluid resuscitation after cardiopulmonary arrest. Patient 1-3: burn, 4-6: sepsis, 7: alcoholic ketoacidosis, 8: resuscitated patient GEDVI of ± 53.5 ml/m 2 and CI of 2.56 ± 0.32 l/min/m 2. The group of mid range NT-proBNP levels ( pg/ml) showed GEDVI of ± ml/m 2 and CI of 4.07 ± 0.61 l/min/m 2. The last group of high NTproBNP levels ( pg/ml) showed GEDVI of 1,253.4 ± ml/m 2 and CI of 4.08 ± 0.48 l/min/m 2. GEDVI increased along with the increasing NTproBNP levels. CI of the group of mid range NT-proBNP levels or the group of high NT-proBNP levels was higher than that of the group of low NT-proBNP levels (p < , for each comparison). CI of the group of mid range NTproBNP levels and high NT-proBNP levels did not significantly differ (p = 0.999). Discussion BNP is synthesized as probnp in cardiomyocytes and is split into BNP having physiological activity through the action of proteolytic enzymes and NT-proBNP. NT-proBNP is a by-product of BNP synthesis and it does not have known physiological activity (Ruskoaho 2003; Vanderheyden et al. 2004). ProBNP is synthesized and secreted in both atria and ventricles under normal conditions. The load on cardiomyocytes (increased left ventricular diastolic pressure, increased left ventricular diastolic volume, left ventricular hypertrophy, wall motion abnormality, myocardial ischemia, etc.) leads to accelerated biosynthesis within 1 hour of stimulus (Nakagawa et al. 1995). BNP is produced both in the atrium and ventricle, and the predominant source of circulating BNP may be either atrium or ventricle depending on the severity and the cause of cardiac disorder (Murakami et al. 2002; Ruskoaho 2003; Omland 2008). The ratio of the peripheral blood concentrations of ANP and BNP under normal conditions is 6 : 1. However, an increase in the severity of heart failure leads to an increase of BNP to exceed that of ANP, resulting in BNP levels greatly exceeding ANP levels in severe cardiac failure cases. The transcription of BNP gene is also increased within 1 hour after stimulation while the transcription of ANP gene is not increased until 3 to 4 hours after stimulation (Nakagawa et al. 1995; Pemberton et al. 2000). The concentration of BNP has a larger dynamic range and reacts more promptly than that of ANP and BNP can sensitively reflect the state of cardiac function at an acute stage (Harada and Nakao 2005). According to the Flank-Starling law, CI depends on end-diastolic wall tension; this wall tension depends on the volume in the heart. The GEDVI, corresponding to ventricular end-diastolic volume, has been shown to be well correlated to CI (Gödje et al. 1998; Sakka et al. 1999). In this assessment (Fig. 3.), there was a positive correlation between GEDVI and CI, which was equivalent to the Flank- Starling law. In addition, the increase of NT-proBNP levels was proportional to the increase of GEDVI as an indicator of cardiac preload, suggesting that NT-proBNP can be used as an indicator of cardiac preload. NT-proBNP is characterized by a reference levels varying with age and gender and is greatly affected in the metabolic pathway by renal dysfunction (Levin et al. 1998; Weber and Hamm 2006). In this study, there were no patients developing renal dysfunction during examination. Further investigation in the future is necessary to determine whether NT-proBNP or BNP is more useful as an indicator of cardiac preload.

4 178 S. Yamanouchi et al. a b c Fig. 2. Relationships between NT-proBNP and measured hemodynamic parameters. Plotted are the values of 39 blood samples. (a) CI (b) GEDVI There were positive correlations of the NT-proBNP levels with the measurements of CI and GEDVI. (c) EVLWI There was no correlation between the NT-proBNP levels and EVLWI. burn, sepsis, alcoholic ketoasidosis, resuscitated patient

5 Blood N-Terminal probnp as an Indicator of Cardiac Preload 179 Fig. 3. Correlation between GEDVI and CI among groups of blood NT-proBNP levels. There was a positive correlation between GEDVI and CI (r = 0.80, p < ) except for the values that were greater than the measurement limit of 3,000 pg/ml for NT-proBNP levels. GEDVI increased along with the increasing NT-proBNP levels. CI of either the group of mid range NT-proBNP levels ( ) or the group of high NT-proBNP levels ( ) was higher than that of the group of low NT-proBNP levels ( ) (p < , for each comparison). CI of the group of mid range NT-proBNP levels and high NT-proBNP levels did not significantly differ (p = 0.999). Most of patients with sepsis had NT-proBNP levels exceeding the measurement limit of 3,000 pg/ml. Although these values increased in sepsis (Varpula et al. 2007), the mechanism for the increase is not clear. This is believed to be related to various causes such as IL-1β, TNF-α (Harada et al. 1999; Court et al. 2002), IL-6 (Tanaka et al. 2004), lipopolysaccharide of Gram-negative bacteria (Tomaru et al. 2002), neurosecretory hormones (Ma et al. 2005; Clerico et al. 2006), hypoxia (Hopkins et al. 2004), renal dysfunction, coagulation disorders and the suppression of cardiac muscle (Varpula et al. 2007). The physiological significance of BNP in sepsis is also unknown. BNP can expand the blood vessel with sepsis and promote hypotension to aggravate the septic shock status. It is unclear whether the increase in BNP with sepsis is related to intractable shock or simply reflects the severity (Varpula et al. 2007). Summary We have provided the evidence that the blood NTproBNP may be a good indicator of cardiac preload in patients with large volume load. The blood NT-proBNP levels were greatly increased in those patients and showed a positive correlation with GEDVI and CI. In addition, blood NT-proBNP is stable and is easily measured at the bedside. We therefore suggest that monitoring blood NT-proBNP levels may be helpful for evaluating cardiac preload in hemodynamically unstable patients. Acknowledgment The authors thank Dr. J. Kitano for his valuable comments. References Chaney, J.C. & Derdak, S. (2002) Minimally invasive hemodynamic monitoring for the intensivist : Current and emerging technology. Crit. Care Med., 30, Clerico, A., Recchia, F.A., Passino, C. & Emdin, M. (2006) Cardiac endocrine function is an essential component of the homeostatic regulation network: physiological and clinical implications. Am. J. Physiol. Heart Circ. Physiol., 290, H17-H29. Court, O., Kumar, A., Parrillo, J.E. & Kumar, A. (2002) Clinical review: Myocardial depression in sepsis and septic shock. Crit. Care., 6, Dastoor, H., Bernieh, B., Boobes, Y., Abouchacra, S., Eltayeb, E., Elhuda, M.N., Kazzam, E., Obineche, E.N. & Nicholls, M.G. (2005) Plasma BNP in patients on maintenance haemodialysis: a guide to management? J. Hypertens., 23, Gödje, O., Peyerl, M., Seebauer, T., Lamm, P. Mair, H. & Reichart, B. (1998) Central venous pressure, pulmonary capillary wedge pressure and intrathoracic blood volumes as preload indicators in cardiac surgery patients. Eur. J. Cardiothorac. Surg., 13, Harada, E., Nakagawa, O., Yoshimura, M., Hamada, M., Nakagawa, M., Mizuno, Y., Shimasaki, Y., Nakayama, M., Yasue, H., Kuwahara, K., Saito, Y. & Nakao, K. (1999) Effect of interleukin-1 beta on cardiac hypertrophy and production of natriuretic peptides in rat cardiocyte culture. J. Mol. Cell. Cardiol., 31, Harada, M. & Nakao, K. (2005) Basic knowledge of BNP. Brain Natriuretic Peptide in Daily Practice, edited by Tsutamoto T. & Saito Y. Nankodo, Tokyo, pp Hopkins, W.E., Chen, Z., Fukagawa, N.K., Hall, C., Knot, H.J. & LeWinter, M.M. (2004) Increased atrial and brain natriuretic peptides in adults with cyanotic congenital heart disease: enhanced understanding of the relationship between hypoxia and natriuretic peptide secretion. Circulation, 109, Januzzi, J.L., van Kimmenade, R., Lainchbury, J., Bayes-Genis, A., Ordonez-Llanos, J., Santalo-Bel, M., Pinto, Y.M. & Richards, M. (2006) NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international

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