Amino-Terminal Pro-Brain-Type Natriuretic Peptide: Heart or Lung Disease in Pediatric Respiratory Distress
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《小儿科》
Institute of Pulmonology Pediatric Cardiology Unit, and Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Pediatric Department, Shaare Zedek Medical Center, Jerusalem, Israel
ABSTRACT
Objectives. The aim of this study was to determine whether plasma levels of amino-terminal pro-brain natriuretic peptide (N-BNP) could differentiate between heart failure and lung disease among infants with acute respiratory distress. In addition, our aim was to determine whether plasma levels of N-BNP could be used to monitor the effects of treatment among infants with heart failure.
Methods. Infants (age range: 1–36 months; median age: 10 months) who presented with respiratory distress underwent physical examination, plasma N-BNP measurement, and echocardiography within 24 hours after admission. Seventeen infants were finally diagnosed with acute heart failure and 18 with acute lung disease. Thirteen healthy infants served as a control group.
Results. Plasma N-BNP levels were significantly higher for the infants with heart failure (median: 18452 pg/mL; range: 5375–99700 pg/mL) than for the infants with lung disease (median: 311 pg/mL; range: 76–1341 pg/mL). Among the infants with heart failure, there was a significant difference in plasma N-BNP levels before and after congestive heart failure treatment.
Conclusion. Among infants with respiratory distress, plasma N-BNP measurements can differentiate between acute heart failure and lung disease and can be used to monitor the effects of treatment for infants with heart failure.
Key Words: amino-terminal pro-brain natriuretic peptide infants respiratory distress congestive heart failure
Abbreviations: BNP, brain natriuretic peptide N-BNP, amino-terminal pro-brain natriuretic peptide CHF, congestive heart failure RD, respiratory distress RSV, respiratory syncytial virus
Respiratory distress (RD) is a common symptom among infants and children. RD is usually caused by lung disease but can also be a result of congestive heart failure (CHF). Symptoms may not be sufficiently accurate to allow a diagnosis of CHF.1 Although echocardiography is a good tool for the diagnosis of left ventricular systolic dysfunction, it is not always available in primary care facilities and is a time- and money-consuming procedure. Children with CHF may develop RD because of a respiratory infection or an exacerbation of their cardiac disease. In these cases, it is often difficult to determine the cause of RD.
Cardiac natriuretic hormones play an important role in the regulation of extracellular fluid volume and blood pressure. These peptide hormones induce natriuresis, diuresis, and vasodilation and act specifically to counter the effects of the renin-angiotensin-aldosterone system.2 Brain natriuretic peptide (BNP) is secreted mainly by cardiac ventricular myocytes in response to stretch, and its plasma levels are related to left ventricular filling pressures.3,4 Among adults, BNP was found to be a good marker for cardiac dysfunction.5–8 BNP is a product of a pro-hormone, pro-BNP, which consists of 108 amino acids. Enzyme processing results in the release of the biologically active, 32-amino acid peptide (BNP) and an amino-terminal fragment, amino-terminal pro-BNP (N-BNP), which has no known biological activity.9–12 It was shown that, like BNP, N-BNP is a sensitive marker of ventricular dysfunction, and it is more stable (half-lives of 20 minutes and 3 hours, respectively).13–16 In the neonatal period, N-BNP levels show marked rapid increases in the first day of life, probably due to the increases in systemic vascular resistance and pulmonary blood flow after birth.17 N-BNP levels start to decrease on the second day and remain constant from the third day of life. Newborns with fetal distress were reported to have up to a 19-fold increase in BNP levels.18 Among premature infants with patent ductus arteriosus, atrial natriuretic peptide and BNP levels were found to be elevated, correlating with the degree of the shunt.19 BNP levels were found to correlate with pulmonary artery pressure among premature infants.20 N-BNP levels were found to be significantly higher among children with CHF than among children without cardiac disease.21 The role of BNP in the diagnosis of CHF among adult patients presenting to the emergency department with acute dyspnea has been reported. Among those patients, BNP was found to be a useful tool for the diagnosis of CHF.22–24 The aim of our study was to assess N-BNP as a biochemical marker of CHF and to determine its value in monitoring the response of CHF to treatment.
METHODS
Plasma N-BNP concentrations were measured at admission for 17 infants with CHF, 18 infants with lung disease, and 13 control infants. All infants underwent clinical assessment, which included measurement of oxygen saturation with pulse oximetry and respiratory rate while breathing room air. All the infants were hospitalized at the Hadassah University Hospital. Local ethics committee approval and informed consent from the parents were obtained.
N-BNP Measurements
Venous blood samples (1–2 mL) were obtained at admission. Plasma was frozen at –20°C and thawed at the time of the assay, which was performed within 1 week. Plasma N-BNP concentrations were determined with an electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany).24 The technician who performed N-BNP measurements was unaware of the clinical state or diagnosis of the patients.
Echocardiography
Two-dimensional echocardiography was used for systolic ventricular evaluation. M-mode measurements of left ventricular function were obtained. Echocardiography was performed on the day blood samples were obtained for all infants with heart disease and for 14 of 18 infants with lung disease. Echocardiography was not performed in the control group.
Echocardiography was not performed again after treatment. The improvement among cardiac patients was quantified only with clinical parameters, ie, room air oxygen saturation and respiratory rate.
Infants With CHF
Seventeen consecutive infants (age range: 1–36 months), most with congenital heart disease, were admitted with acute RD. All these patients were diagnosed as having acute CHF by a senior pediatric cardiologist (Z.P., A.J.J.T.R., or A.N.), on the basis of clinical symptoms and echocardiographic findings, before they entered the study. The cardiologists were not aware of plasma N-BNP levels.
Three infants had mitral regurgitation. One infant developed ischemic heart disease because of coronary artery occlusion after surgical correction for transposition of the great arteries. Two infants had atrioventricular canal, 3 had ventricular septal defect, 1 had hypertrophic obstructive cardiomyopathy, 1 had truncus arteriosus with pulmonary hypertension, and 1 had total anomalous pulmonary venous return. One infant developed severe CHF because of systemic renovascular hypertension (with normal creatinine clearance). One infant had acute myocarditis, and 1 had tetralogy of Fallot after a large Blalock-Taussig shunt. One patient developed severe pulmonary hypertension because of pulmonary embolism, and 1 infant with Down syndrome developed a pulmonary hypertension crisis after repair of the atrioventricular canal.
CHF treatment included diuretics (furosemide and spironolactone), with or without digoxin. Five of the children with CHF were already receiving similar treatment, and the doses were increased during hospitalization. For 13 infants of the cardiac group, plasma N-BNP levels, respiratory rate, and oxygen saturation were also measured after treatment for CHF. The efficacy of the CHF treatment was measured only by clinical improvement and not echocardiography. Four of the cardiac patients also had pneumonia.
Infants With Lung Disease
Eighteen consecutive infants (age range: 1–19 months) with acute RD had respiratory syncytial virus (RSV) bronchiolitis (n = 10), RSV-negative bronchiolitis (n = 2), adenovirus pneumonia (n = 1), lobar pneumonia (n = 1), acute bronchitis (n = 3), and acute laryngitis (n = 1). All these infants were healthy infants before the present episode, with no chronic disease.
Control Infants
Thirteen infants (age range: 1–36 months) free of heart and lung disease were admitted for elective surgery or treatment of minor trauma and served as control subjects.
Statistical Analyses
All data are presented as median or mean values with SD. Values of N-BNP levels were non-normally distributed, and the Mann-Whitney rank-sum test was used for comparisons between groups. Analysis of variance and paired and unpaired t tests were used as needed. P < .05 was considered significant.
RESULTS
Oxygen saturation at admission (while breathing room air) was significantly lower in the cardiac and lung groups, compared with the control group (P < .001). The respiratory rate at admission was significantly higher in the cardiac and lung groups, compared with the control group (P < .001). There were no significant differences in oxygen saturation and respiratory rate between the cardiac and lung groups. Echocardiography performed for the infants with CHF at admission showed mainly pressure or volume overload of the left (n = 15) or right (n = 4) heart.
Plasma N-BNP levels for the infants with acute CHF (median: 18452 pg/mL; range: 5736–99700 pg/mL) were significantly higher (P < .001), compared (Mann-Whitney rank-sum test) with the infants with acute lung disease (median: 311 pg/mL; range: 76–1341 pg/mL) and the healthy control subjects (median: 89 pg/mL; range: 88–292 pg/mL) (Table 2 and Fig 1). There was no significant difference between N-BNP levels in the lung and control groups. Receiver operating characteristic curve analysis of the diagnosis of CHF was performed. The area under the receiver operating characteristic curve was 1.0, meaning that, for the present sample of data, the accuracy of the test in differentiating cardiac disease from lung disease and the control condition was 100%. The highest N-BNP level among the lung patients was 1341 pg/mL, and the lowest level among the cardiac patients was 5375 pg/mL. The calculated cutoff N-BNP value differentiating cardiac patients from control and lung patients, according to our data, was 2940 pg/mL. For 13 of 17 infants with CHF, plasma N-BNP levels, room air oxygen saturation, and respiratory rate were significantly (P < .001) improved after CHF treatment (Figs 2 and 3).
DISCUSSION
In this prospective study, we showed that plasma N-BNP levels could differentiate CHF from lung disease among infants and children who were evaluated for acute RD in the emergency department. The clinical diagnosis of CHF, when based on a careful history, distinctive signs, and radiographic evidence of pulmonary venous congestion, may be difficult. This is especially true for patients with chronic CHF and a concomitant disorder, such as pneumonia, or infants and children during their first acute CHF exacerbation (which also requires echocardiography for diagnosis). Recognition of the early manifestations of cardiac failure may be difficult in infants presenting with acute dyspnea, but the diagnosis is critical for proper treatment. Although echocardiography is a good tool for diagnosing left ventricular systolic dysfunction, it is usually not available in an emergency department setting. Our findings for infants and young children, as shown previously for adults, offer a new, additional diagnostic tool for fast accurate diagnosis of CHF. According to our results, plasma levels of N-BNP among infants with acute lung diseases were not significantly different from the levels among normal children, but plasma levels among cardiac patients were significantly higher (P < .001) than the levels in the 2 other groups. The calculated cutoff N-BNP value differentiating cardiac patients from control and lung patients was 2940 pg. We therefore suggest this value as a cutoff value between pediatric cardiac and lung patients.
Among adults, BNP levels have not been found to be significantly higher among patients with acute respiratory illnesses, compared with healthy control subjects.6 In our study, we found similar results. We found a slight (nonsignificant) increase in mean N-BNP levels among the children with lung disease, compared with the control subjects (Table 1).
In our study, plasma N-BNP levels were also found to be a reliable indicator of clinical improvement after therapy. We showed a significant decrease in plasma N-BNP levels, which correlated with a significant increase in room air oxygen saturation and a significant decrease in respiratory rate after treatment for CHF. This was probably a response to the diuretic treatment, which decreased cardiac pressure and volume load. These findings suggest that plasma N-BNP levels can be used as a marker for improved cardiac function among infants and children with CHF and can save repeating echocardiography.
There are several limitations to the use of N-BNP as an aid in the diagnosis of CHF. First, patients with CHF can also suffer from a concomitant disorder such as pneumonia. In our study, 4 cardiac patients had pneumonia and were treated with both diuretics and antibiotics. Their plasma N-BNP levels were high at admission and decreased after treatment. Therefore, a very high level of N-BNP, although specific for decompensated CHF, does not exclude the presence of other diseases. Second, patients with chronic CHF may have persistent high plasma N-BNP levels.21 The proper assessment of these patients during an acute exacerbation requires comparison of their actual N-BNP levels with their baseline levels. We evaluated 2 infants with chronic CHF (not included in this study because they represented a small group) in the emergency department during an acute episode of RD and acute RSV bronchiolitis. Their high plasma N-BNP levels measured in the emergency department were similar to their previous baseline levels. Echocardiography performed during the acute illness showed a similar chronic CHF state. One of these 2 infants had a ventricular septal defect, and his baseline N-BNP level was 1212 pg/mL. During the acute respiratory event, the N-BNP level was 1274 pg/mL. The second patient had a complete atrioventricular canal. His baseline N-BNP level was 7907 pg/mL, and the level during the acute RSV bronchiolitis was 7018 pg/mL. In conclusion, our findings suggest that rapid assays of plasma N-BNP levels may assist pediatricians with the differential diagnosis of patients with acute RD, defining cardiac or lung origin and allowing subsequent accurate management.
FOOTNOTES
Accepted Sep 14, 2004.
No conflict of interest declared.
REFERENCES
Stevenson LW, Perloff JK. The limited availability of physical signs for estimating hemodynamics in chronic heart failure. JAMA. 1989;261 :884 –888
Levin E, Gardner D, Samson W. Natriuretic peptides. N Engl J Med. 1998;339 :321 –327
Sudoh T, Kanagawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature. 1988;332 :78 –81
Kjaer A, Hesse B. Heart failure and neuroendocrine activation: diagnostic, prognostic and therapeutic perspectives. Clin Physiol. 2001;6 :661 –672
Yoshimura M, Yasue H, Okumura K, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation. 1993;87 :464 –469
Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347 :161 –167
Kazanegra R, Cheng V, Garcia A, et al. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail. 2001;7 :21 –29
Richards AM, Crozier IG, Yaandle TG, Espiner EA, Ikram H, Nicholls MG. Brain natriuretic factor: regional plasma concentrations and correlations with hemodynamic state in cardiac disease. Br Heart J. 1993;69 :414 –417
Kelly R, Struthers AD. Are natriuretic peptides clinically useful as markers of heart failure Ann Clin Biochem. 2001;38 :94 –102
Karl J, Borgya A, Gallusser A, et al. Development of a novel N-terminal-pro BNP (NT-pro BNP) assay with a low detection limit. Scand J Clin Lab Invest. 1999;230 :177 –181
Downie PF, Talwar S, Squire IB, Davies JE, Barnett DB, Ng LL. Assessment of the stability of N-terminal pro-brain natriuretic peptide in vitro: implications for assessment of left ventricular dysfunction. Clin Sci (Lond). 1999;97 :255 –258
Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohumoral predictors of left ventricular function and prognosis after myocardial infarction. Circulation. 1998;97 :1921 –1929
Hunt PJ, Yandle TG, Nichols MG, Richards AM, Espiner EA. The amino-terminal portion of pro-brain natriuretic peptide (pro-BNP) circulates in human plasma. Biochem Biophys Res Commun. 1995;214 :1175 –1183
Daggubati S, Parks JR, Overton RM, Cintron G, Schocken DD, Vesely DL. Adrenomedullin, endothelin, neuropeptide Y, atrial, brain, and C-natriuretic prohormone peptides compared as early heart failure indicators. Cardivasc Res. 1997;36 :246 –255
Hunt PJ, Richards AM, Nicholls MG, Yandle TG, Doughty RN, Espiner EA. Immunoreactive amino-terminal pro-brain natruretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endocrinol (Oxf). 1997;47 :287 –296
Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102 :865 –870
Mir TS, Laux R, Hellwege HH, et al. Plasma concentrations of amino-terminal proatrial natriuretic peptide and amino-terminal probrain natriuretic peptide in healthy neonates: marked and rapid increase after birth. Pediatrics. 2003;112 :896 –899
Itoh H, Sagawa N, Hasegawa M, et al. Brain natriuretic peptide levels in the umbilical venous plasma are elevated in fetal distress. Biol Neonate. 1993;64 :18 –25
Holmstrom H, Hall C, Thaulow E. Plasma levels of natriuretic peptides and hemodynamic assessment of patent ductus arteriosus in preterm infants. Acta Pediatr. 2001;90 :184 –191
Ikemoto Y, Nogi S, Teraguchi M, Kojima T, Hirata Y, Kobayashi Y. Early changes in plasma brain and atrial natriuretic peptides in premature infants: correlation with pulmonary arterial pressure. Early Hum Dev. 1996;46 :55 –62
Morrison LK, Harrison A, Krishnaswamy P, Kasanegra R, Clopton P, Maisel A. Utility of a rapid B-natriuretic peptide assay in differentiate congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol. 2002;39 :202 –209
Davis M, Espiner E, Richards G, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343 :440 –444
Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med. 2004;350 :647 –654(Shlomo Cohen, MD, Chaim S)
Pediatric Department, Shaare Zedek Medical Center, Jerusalem, Israel
ABSTRACT
Objectives. The aim of this study was to determine whether plasma levels of amino-terminal pro-brain natriuretic peptide (N-BNP) could differentiate between heart failure and lung disease among infants with acute respiratory distress. In addition, our aim was to determine whether plasma levels of N-BNP could be used to monitor the effects of treatment among infants with heart failure.
Methods. Infants (age range: 1–36 months; median age: 10 months) who presented with respiratory distress underwent physical examination, plasma N-BNP measurement, and echocardiography within 24 hours after admission. Seventeen infants were finally diagnosed with acute heart failure and 18 with acute lung disease. Thirteen healthy infants served as a control group.
Results. Plasma N-BNP levels were significantly higher for the infants with heart failure (median: 18452 pg/mL; range: 5375–99700 pg/mL) than for the infants with lung disease (median: 311 pg/mL; range: 76–1341 pg/mL). Among the infants with heart failure, there was a significant difference in plasma N-BNP levels before and after congestive heart failure treatment.
Conclusion. Among infants with respiratory distress, plasma N-BNP measurements can differentiate between acute heart failure and lung disease and can be used to monitor the effects of treatment for infants with heart failure.
Key Words: amino-terminal pro-brain natriuretic peptide infants respiratory distress congestive heart failure
Abbreviations: BNP, brain natriuretic peptide N-BNP, amino-terminal pro-brain natriuretic peptide CHF, congestive heart failure RD, respiratory distress RSV, respiratory syncytial virus
Respiratory distress (RD) is a common symptom among infants and children. RD is usually caused by lung disease but can also be a result of congestive heart failure (CHF). Symptoms may not be sufficiently accurate to allow a diagnosis of CHF.1 Although echocardiography is a good tool for the diagnosis of left ventricular systolic dysfunction, it is not always available in primary care facilities and is a time- and money-consuming procedure. Children with CHF may develop RD because of a respiratory infection or an exacerbation of their cardiac disease. In these cases, it is often difficult to determine the cause of RD.
Cardiac natriuretic hormones play an important role in the regulation of extracellular fluid volume and blood pressure. These peptide hormones induce natriuresis, diuresis, and vasodilation and act specifically to counter the effects of the renin-angiotensin-aldosterone system.2 Brain natriuretic peptide (BNP) is secreted mainly by cardiac ventricular myocytes in response to stretch, and its plasma levels are related to left ventricular filling pressures.3,4 Among adults, BNP was found to be a good marker for cardiac dysfunction.5–8 BNP is a product of a pro-hormone, pro-BNP, which consists of 108 amino acids. Enzyme processing results in the release of the biologically active, 32-amino acid peptide (BNP) and an amino-terminal fragment, amino-terminal pro-BNP (N-BNP), which has no known biological activity.9–12 It was shown that, like BNP, N-BNP is a sensitive marker of ventricular dysfunction, and it is more stable (half-lives of 20 minutes and 3 hours, respectively).13–16 In the neonatal period, N-BNP levels show marked rapid increases in the first day of life, probably due to the increases in systemic vascular resistance and pulmonary blood flow after birth.17 N-BNP levels start to decrease on the second day and remain constant from the third day of life. Newborns with fetal distress were reported to have up to a 19-fold increase in BNP levels.18 Among premature infants with patent ductus arteriosus, atrial natriuretic peptide and BNP levels were found to be elevated, correlating with the degree of the shunt.19 BNP levels were found to correlate with pulmonary artery pressure among premature infants.20 N-BNP levels were found to be significantly higher among children with CHF than among children without cardiac disease.21 The role of BNP in the diagnosis of CHF among adult patients presenting to the emergency department with acute dyspnea has been reported. Among those patients, BNP was found to be a useful tool for the diagnosis of CHF.22–24 The aim of our study was to assess N-BNP as a biochemical marker of CHF and to determine its value in monitoring the response of CHF to treatment.
METHODS
Plasma N-BNP concentrations were measured at admission for 17 infants with CHF, 18 infants with lung disease, and 13 control infants. All infants underwent clinical assessment, which included measurement of oxygen saturation with pulse oximetry and respiratory rate while breathing room air. All the infants were hospitalized at the Hadassah University Hospital. Local ethics committee approval and informed consent from the parents were obtained.
N-BNP Measurements
Venous blood samples (1–2 mL) were obtained at admission. Plasma was frozen at –20°C and thawed at the time of the assay, which was performed within 1 week. Plasma N-BNP concentrations were determined with an electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany).24 The technician who performed N-BNP measurements was unaware of the clinical state or diagnosis of the patients.
Echocardiography
Two-dimensional echocardiography was used for systolic ventricular evaluation. M-mode measurements of left ventricular function were obtained. Echocardiography was performed on the day blood samples were obtained for all infants with heart disease and for 14 of 18 infants with lung disease. Echocardiography was not performed in the control group.
Echocardiography was not performed again after treatment. The improvement among cardiac patients was quantified only with clinical parameters, ie, room air oxygen saturation and respiratory rate.
Infants With CHF
Seventeen consecutive infants (age range: 1–36 months), most with congenital heart disease, were admitted with acute RD. All these patients were diagnosed as having acute CHF by a senior pediatric cardiologist (Z.P., A.J.J.T.R., or A.N.), on the basis of clinical symptoms and echocardiographic findings, before they entered the study. The cardiologists were not aware of plasma N-BNP levels.
Three infants had mitral regurgitation. One infant developed ischemic heart disease because of coronary artery occlusion after surgical correction for transposition of the great arteries. Two infants had atrioventricular canal, 3 had ventricular septal defect, 1 had hypertrophic obstructive cardiomyopathy, 1 had truncus arteriosus with pulmonary hypertension, and 1 had total anomalous pulmonary venous return. One infant developed severe CHF because of systemic renovascular hypertension (with normal creatinine clearance). One infant had acute myocarditis, and 1 had tetralogy of Fallot after a large Blalock-Taussig shunt. One patient developed severe pulmonary hypertension because of pulmonary embolism, and 1 infant with Down syndrome developed a pulmonary hypertension crisis after repair of the atrioventricular canal.
CHF treatment included diuretics (furosemide and spironolactone), with or without digoxin. Five of the children with CHF were already receiving similar treatment, and the doses were increased during hospitalization. For 13 infants of the cardiac group, plasma N-BNP levels, respiratory rate, and oxygen saturation were also measured after treatment for CHF. The efficacy of the CHF treatment was measured only by clinical improvement and not echocardiography. Four of the cardiac patients also had pneumonia.
Infants With Lung Disease
Eighteen consecutive infants (age range: 1–19 months) with acute RD had respiratory syncytial virus (RSV) bronchiolitis (n = 10), RSV-negative bronchiolitis (n = 2), adenovirus pneumonia (n = 1), lobar pneumonia (n = 1), acute bronchitis (n = 3), and acute laryngitis (n = 1). All these infants were healthy infants before the present episode, with no chronic disease.
Control Infants
Thirteen infants (age range: 1–36 months) free of heart and lung disease were admitted for elective surgery or treatment of minor trauma and served as control subjects.
Statistical Analyses
All data are presented as median or mean values with SD. Values of N-BNP levels were non-normally distributed, and the Mann-Whitney rank-sum test was used for comparisons between groups. Analysis of variance and paired and unpaired t tests were used as needed. P < .05 was considered significant.
RESULTS
Oxygen saturation at admission (while breathing room air) was significantly lower in the cardiac and lung groups, compared with the control group (P < .001). The respiratory rate at admission was significantly higher in the cardiac and lung groups, compared with the control group (P < .001). There were no significant differences in oxygen saturation and respiratory rate between the cardiac and lung groups. Echocardiography performed for the infants with CHF at admission showed mainly pressure or volume overload of the left (n = 15) or right (n = 4) heart.
Plasma N-BNP levels for the infants with acute CHF (median: 18452 pg/mL; range: 5736–99700 pg/mL) were significantly higher (P < .001), compared (Mann-Whitney rank-sum test) with the infants with acute lung disease (median: 311 pg/mL; range: 76–1341 pg/mL) and the healthy control subjects (median: 89 pg/mL; range: 88–292 pg/mL) (Table 2 and Fig 1). There was no significant difference between N-BNP levels in the lung and control groups. Receiver operating characteristic curve analysis of the diagnosis of CHF was performed. The area under the receiver operating characteristic curve was 1.0, meaning that, for the present sample of data, the accuracy of the test in differentiating cardiac disease from lung disease and the control condition was 100%. The highest N-BNP level among the lung patients was 1341 pg/mL, and the lowest level among the cardiac patients was 5375 pg/mL. The calculated cutoff N-BNP value differentiating cardiac patients from control and lung patients, according to our data, was 2940 pg/mL. For 13 of 17 infants with CHF, plasma N-BNP levels, room air oxygen saturation, and respiratory rate were significantly (P < .001) improved after CHF treatment (Figs 2 and 3).
DISCUSSION
In this prospective study, we showed that plasma N-BNP levels could differentiate CHF from lung disease among infants and children who were evaluated for acute RD in the emergency department. The clinical diagnosis of CHF, when based on a careful history, distinctive signs, and radiographic evidence of pulmonary venous congestion, may be difficult. This is especially true for patients with chronic CHF and a concomitant disorder, such as pneumonia, or infants and children during their first acute CHF exacerbation (which also requires echocardiography for diagnosis). Recognition of the early manifestations of cardiac failure may be difficult in infants presenting with acute dyspnea, but the diagnosis is critical for proper treatment. Although echocardiography is a good tool for diagnosing left ventricular systolic dysfunction, it is usually not available in an emergency department setting. Our findings for infants and young children, as shown previously for adults, offer a new, additional diagnostic tool for fast accurate diagnosis of CHF. According to our results, plasma levels of N-BNP among infants with acute lung diseases were not significantly different from the levels among normal children, but plasma levels among cardiac patients were significantly higher (P < .001) than the levels in the 2 other groups. The calculated cutoff N-BNP value differentiating cardiac patients from control and lung patients was 2940 pg. We therefore suggest this value as a cutoff value between pediatric cardiac and lung patients.
Among adults, BNP levels have not been found to be significantly higher among patients with acute respiratory illnesses, compared with healthy control subjects.6 In our study, we found similar results. We found a slight (nonsignificant) increase in mean N-BNP levels among the children with lung disease, compared with the control subjects (Table 1).
In our study, plasma N-BNP levels were also found to be a reliable indicator of clinical improvement after therapy. We showed a significant decrease in plasma N-BNP levels, which correlated with a significant increase in room air oxygen saturation and a significant decrease in respiratory rate after treatment for CHF. This was probably a response to the diuretic treatment, which decreased cardiac pressure and volume load. These findings suggest that plasma N-BNP levels can be used as a marker for improved cardiac function among infants and children with CHF and can save repeating echocardiography.
There are several limitations to the use of N-BNP as an aid in the diagnosis of CHF. First, patients with CHF can also suffer from a concomitant disorder such as pneumonia. In our study, 4 cardiac patients had pneumonia and were treated with both diuretics and antibiotics. Their plasma N-BNP levels were high at admission and decreased after treatment. Therefore, a very high level of N-BNP, although specific for decompensated CHF, does not exclude the presence of other diseases. Second, patients with chronic CHF may have persistent high plasma N-BNP levels.21 The proper assessment of these patients during an acute exacerbation requires comparison of their actual N-BNP levels with their baseline levels. We evaluated 2 infants with chronic CHF (not included in this study because they represented a small group) in the emergency department during an acute episode of RD and acute RSV bronchiolitis. Their high plasma N-BNP levels measured in the emergency department were similar to their previous baseline levels. Echocardiography performed during the acute illness showed a similar chronic CHF state. One of these 2 infants had a ventricular septal defect, and his baseline N-BNP level was 1212 pg/mL. During the acute respiratory event, the N-BNP level was 1274 pg/mL. The second patient had a complete atrioventricular canal. His baseline N-BNP level was 7907 pg/mL, and the level during the acute RSV bronchiolitis was 7018 pg/mL. In conclusion, our findings suggest that rapid assays of plasma N-BNP levels may assist pediatricians with the differential diagnosis of patients with acute RD, defining cardiac or lung origin and allowing subsequent accurate management.
FOOTNOTES
Accepted Sep 14, 2004.
No conflict of interest declared.
REFERENCES
Stevenson LW, Perloff JK. The limited availability of physical signs for estimating hemodynamics in chronic heart failure. JAMA. 1989;261 :884 –888
Levin E, Gardner D, Samson W. Natriuretic peptides. N Engl J Med. 1998;339 :321 –327
Sudoh T, Kanagawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature. 1988;332 :78 –81
Kjaer A, Hesse B. Heart failure and neuroendocrine activation: diagnostic, prognostic and therapeutic perspectives. Clin Physiol. 2001;6 :661 –672
Yoshimura M, Yasue H, Okumura K, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation. 1993;87 :464 –469
Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347 :161 –167
Kazanegra R, Cheng V, Garcia A, et al. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail. 2001;7 :21 –29
Richards AM, Crozier IG, Yaandle TG, Espiner EA, Ikram H, Nicholls MG. Brain natriuretic factor: regional plasma concentrations and correlations with hemodynamic state in cardiac disease. Br Heart J. 1993;69 :414 –417
Kelly R, Struthers AD. Are natriuretic peptides clinically useful as markers of heart failure Ann Clin Biochem. 2001;38 :94 –102
Karl J, Borgya A, Gallusser A, et al. Development of a novel N-terminal-pro BNP (NT-pro BNP) assay with a low detection limit. Scand J Clin Lab Invest. 1999;230 :177 –181
Downie PF, Talwar S, Squire IB, Davies JE, Barnett DB, Ng LL. Assessment of the stability of N-terminal pro-brain natriuretic peptide in vitro: implications for assessment of left ventricular dysfunction. Clin Sci (Lond). 1999;97 :255 –258
Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohumoral predictors of left ventricular function and prognosis after myocardial infarction. Circulation. 1998;97 :1921 –1929
Hunt PJ, Yandle TG, Nichols MG, Richards AM, Espiner EA. The amino-terminal portion of pro-brain natriuretic peptide (pro-BNP) circulates in human plasma. Biochem Biophys Res Commun. 1995;214 :1175 –1183
Daggubati S, Parks JR, Overton RM, Cintron G, Schocken DD, Vesely DL. Adrenomedullin, endothelin, neuropeptide Y, atrial, brain, and C-natriuretic prohormone peptides compared as early heart failure indicators. Cardivasc Res. 1997;36 :246 –255
Hunt PJ, Richards AM, Nicholls MG, Yandle TG, Doughty RN, Espiner EA. Immunoreactive amino-terminal pro-brain natruretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endocrinol (Oxf). 1997;47 :287 –296
Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102 :865 –870
Mir TS, Laux R, Hellwege HH, et al. Plasma concentrations of amino-terminal proatrial natriuretic peptide and amino-terminal probrain natriuretic peptide in healthy neonates: marked and rapid increase after birth. Pediatrics. 2003;112 :896 –899
Itoh H, Sagawa N, Hasegawa M, et al. Brain natriuretic peptide levels in the umbilical venous plasma are elevated in fetal distress. Biol Neonate. 1993;64 :18 –25
Holmstrom H, Hall C, Thaulow E. Plasma levels of natriuretic peptides and hemodynamic assessment of patent ductus arteriosus in preterm infants. Acta Pediatr. 2001;90 :184 –191
Ikemoto Y, Nogi S, Teraguchi M, Kojima T, Hirata Y, Kobayashi Y. Early changes in plasma brain and atrial natriuretic peptides in premature infants: correlation with pulmonary arterial pressure. Early Hum Dev. 1996;46 :55 –62
Morrison LK, Harrison A, Krishnaswamy P, Kasanegra R, Clopton P, Maisel A. Utility of a rapid B-natriuretic peptide assay in differentiate congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol. 2002;39 :202 –209
Davis M, Espiner E, Richards G, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343 :440 –444
Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med. 2004;350 :647 –654(Shlomo Cohen, MD, Chaim S)