Published online September 11, 2006
PEDIATRICS Vol. 118 No. 4 October 2006, pp. e1165-e1168 (doi:10.1542/peds.2006-0569)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fried, I.
Right arrow Articles by Nir, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fried, I.
Right arrow Articles by Nir, A.
Related Collections
Right arrow Heart & Blood Vessels

ARTICLE

Comparison of N-terminal Pro-B-Type Natriuretic Peptide Levels in Critically Ill Children With Sepsis Versus Acute Left Ventricular Dysfunction

Iris Fried, MDa, Benjamin Bar-Oz, MDb, Nurit Algur, MScc, Elchanan Fried, MDd, Sagui Gavri, MDe, Ido Yatsiv, MDf, Zeev Perles, MDe, Azaria J. J. T. Rein, MDe, Zeev Zonis, MDg, Roman Bass, MDf and Amiram Nir, MDh

a Departments of Pediatrics
b Neonatology
d Internal Medicine
e Pediatric Cardiology Unit
f Pediatric Intensive Care Unit, Hadassah and the Hebrew University Medical Center, Jerusalem, Israel
c Biochemistry Laboratory
h Pediatric Cardiology Unit, Shaare Zedek Medical Center, Jerusalem, Israel
g Pediatric Intensive Care Unit, Western Galilee Hospital, Naharia, Israel


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. N-terminal pro-B-type natriuretic peptide has been shown to be a marker for cardiac dysfunction. The peptide level is also elevated in patients with sepsis. The purpose of this study was to assess whether N-terminal pro-B-type natriuretic peptide levels can differentiate pediatric patients with sepsis from patients with acute left ventricular dysfunction.

PATIENTS AND METHODS. Pediatric patients admitted to an ICU with sepsis or acute left ventricular dysfunction were evaluated clinically, and the grade of systemic inflammatory-response syndrome was determined. Echocardiography was performed, and their levels of N-terminal pro-B-type natriuretic peptide were measured. The N-terminal pro-B-type natriuretic peptide level was also measured in patients with simple febrile illness.

RESULTS. There were 10 patients with sepsis and 10 with acute left ventricular dysfunction. The age of the patients was similar, and systemic inflammatory-response syndrome grading was not different (sepsis: 2.8 ± 0.4; acute left ventricular dysfunction: 2.6 ± 0.7). N-terminal pro-B-type natriuretic peptide levels were elevated in patients with sepsis (median: 6064 pg/mL; range: 495–60417 pg/mL) but were significantly higher in patients with acute left ventricular dysfunction (median: 65630 pg/mL; range: 15125–288000). The area under the receiver operating characteristics curve for the diagnosis of acute left ventricular dysfunction was 0.9. N-terminal pro-B-type natriuretic peptide levels of patients with sepsis and impaired systolic function were not different from those of patients with sepsis and normal systolic function. The N-terminal pro-B-type natriuretic peptide levels of 20 patients with simple febrile illness were significantly lower.

CONCLUSIONS. N-terminal pro-B-type natriuretic peptide levels are elevated in pediatric patients with sepsis but are higher in some, but not all, patients with acute left ventricular dysfunction. The overlap between N-terminal pro-B-type natriuretic peptide levels in sepsis and acute left ventricular dysfunction precludes the use of the peptide's level as a sole means to differentiate between these conditions. Excessive elevation in N-terminal pro-B-type natriuretic peptide levels, however, suggests cardiac etiology for acute hemodynamic deterioration in infants and children.

Key Words: B-type natriuretic peptide • left ventricular dysfunction • sepsis • infants • children

Abbreviations: BNP—B-type natriuretic peptide • NT-proBNP—N-terminal pro-B-type natriuretic peptide • LVD—left ventricular dysfunction • SIRS—systemic inflammatory-response syndrome

B-type natriuretic peptide (BNP), a member of the natriuretic peptide family, is secreted from cardiac myocytes in response to muscle stretch.1 In recent years, BNP and the N-terminal segment of its prohormone, NT-proBNP, were shown to be very sensitive biochemical markers for cardiac dysfunction both in adults and in children.2 We have reported excessive elevation of NT-proBNP levels in pediatric patients with acute left ventricular dysfunction (LVD).3 Studies in the adult population have found elevated BNP levels in patients with sepsis.4,5 The purpose of this study was to (1) compare NT-proBNP levels in pediatric patients with acute LVD to levels in patients with similar hemodynamic status resulting from sepsis and (2) assess whether NT-proBNP levels can differentiate these 2 disease states.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The study was approved by the institutional ethics committee. Informed consent was obtained from parents of patients with sepsis. In patients with acute LVD, NT-proBNP levels were measured as part of the cardiac evaluation.

Patients admitted to 3 PICUs were included. Some of the patients were included in previous publications of the group. Patients with chronic cardiac or renal diseases were excluded. Patients were evaluated clinically and graded by the systemic inflammatory-response syndrome (SIRS) scale.6 SIRS 1 is defined as 2 of the following: fever, tachypnea, tachycardia, and leukocytosis or leukopenia. SIRS 2 is a state with impaired perfusion as manifested by 1 of the following: impaired conscious state, oliguria, hypoxemia, or lactic acidosis. SIRS 3 is an inflammatory state accompanied by shock. Sepsis is defined as SIRS with clear evidence of infection. NT-proBNP levels and echocardiography were performed within 24 hours of the diagnosis of sepsis or acute LVD. Patients were treated as indicated according to their clinical status.

Echocardiography was performed by pediatric cardiologists unaware of the NT-proBNP levels. Systolic left ventricular function was assessed by using M-mode and expressed as shortening fraction. Patients with LVD had a follow-up echocardiogram. Some patients with a definite diagnosis of sepsis had impaired cardiac function; however, the predominant clinical presentation was that of sepsis.

A third group consisted of hemodynamically stable pediatric patients with no history or signs of heart disease who presented with a simple febrile illness. In this group, NT-proBNP levels were measured in plasma that remained after a routine blood count was performed.

For measurement of the NT-proBNP level, blood was collected in tubes containing EDTA. Plasma was separated and stored at –20°C. An electrochemiluminescence immunoassay was performed with the Elecsys system 1010/2010 using the proBNP kit (Roche, Mannheim, Germany). Elecsys proBNP contains polyclonal antibodies that recognize epitopes located in the N-terminal part (1–76) of proBNP (1–108). The assay range is 5 to 35000 pg/mL; higher values were obtained by dilution. The proBNP kit is unaffected by icterus (bilirubin < 35 mg/dL). No cross reactivity was reported with BNP.

Statistical analysis was performed by using the SPSS (SPSS Inc, Chicago, IL). When data were not normally distributed, differences between groups were calculated by using the Mann-Whitney rank-sum test. Correlations were calculated with Pearson's correlation test.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
There were 10 patients with sepsis and 10 with acute LVD. Table 1 shows the demographic and clinical characteristics of these patients, as well as their echocardiographically determined left ventricular systolic function and NT-proBNP levels. As displayed, there was no difference in the age of the groups. The clinical status, as reflected by the SIRS grade, was not different (P = .49). In the LVD group, 4 patients needed mechanical ventilation and 7 received intravenous inotropic support. In the sepsis group, 7 patients needed mechanical ventilation and 6 received intravenous inotropic support. One patient in each group died.


View this table:
[in this window]
[in a new window]
  		TABLE 1 Clinical and Echocardiographic Characteristics and NT-proBNP Levels of Patients With Sepsis and Acute LVD

 
NT-proBNP levels were elevated in both groups. They were markedly elevated in patients with sepsis (median: 6064 pg/mL; range: 495–60417 pg/mL) but significantly higher in patients with acute LVD (median: 65630 pg/mL; range: 15125–288000 pg/mL; P = .01) (Fig 1). The area under the receiver operating characteristic curve for the diagnosis of LVD in these patients was 0.9 (95% confidence interval: 0.77–1.0). NT-proBNP levels <11000 pg/mL had a 100% negative predictive value for acute LVD in this group of patients. The median NT-proBNP levels of 20 patients with simple febrile illness was 280 pg/mL (range: 12–1970 pg/mL), significantly lower than those in both study groups (P = .002 versus the sepsis group) (Fig 1).


Figure 1
View larger version (12K):
[in this window]
[in a new window]
  		FIGURE 1 Plasma NT-proBNP levels (displayed on a logarithmic scale) of children with simple febrile illness (fever), children with sepsis, and children with acute LVD. Bars represent the median and 5th, 25th,75th, and 95th percentiles; dots represent individual outliers.

 
Left ventricular function was, per definition, impaired in all patients with LVD (mean shortening fraction: 14.9%; range: 10%–21%) and significantly better in the patients with sepsis (mean shortening fraction: 29%; range: 19%–45%; P = .001). Five of the patients with sepsis had transiently impaired left ventricular function (shortening fraction: 19%–23%), but these patients did not have higher NT-proBNP levels than the patients with sepsis who had normal left ventricular function (low shortening fraction: 16816 ± 10095 pg/mL [mean ± SE]; normal shortening fraction: 17447 ± 11073 pg/mL; P = .96).

The impact of renal failure on NT-proBNP levels was addressed: in both groups 50% of the patients had acute renal failure, as reflected by plasma creatinine elevation. When patients with renal failure were excluded, NT-proBNP levels were still higher in the children with acute LVD (median: 47120 pg/mL) than in the children with sepsis (median: 2527 pg/mL; P = .03). Among all patients, there was no correlation between creatinine and NT-proBNP levels (P = .7; r = 0.08). Of the 5 patients with sepsis and normal renal function, 4 had normal systolic left ventricular function. Their NT-proBNP levels were elevated (60417, 7558, 1952, and 1115 pg/mL). The 2 patients who died (1 in every group) had NT-proBNP levels below the median of their respective groups (sepsis: 2527 pg/mL; acute LVD: 63260 pg/mL).


   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Elevation of the NT-proBNP level in pediatric and adult patients with cardiac dysfunction has been reported previously.3,7,8 Like others,5,9 we found elevated levels in patients with sepsis. In patients with cardiac dysfunction and similar hemodynamic status, as expressed by SIRS grade, NT-proBNP levels were significantly higher than in patients with sepsis. These findings indicate that NT-proBNP may serve as a marker for a cardiac cause of preshock or shock states. We found a threshold of 11000 pg/mL as the level above which one may suspect cardiac origin in pediatric patients with hemodynamic compromise. This figure should be considered with caution because of the small number of patients in the study groups, but it is significantly higher than NT-proBNP levels in those with stable hemodynamic conditions.

The finding of high levels of NT-proBNP in patients with sepsis needs to be addressed. In adult patients with septic shock, 44% were found to have cardiac dysfunction.10 In our study, 50% of the patients with sepsis were found to have impaired left ventricular function, consistent with the reports in adults. It is interesting to note that NT-proBNP levels of patients with sepsis and impaired systolic function were not different from those of patients with sepsis and normal systolic function.

In this group of patients there were 4 with sepsis and normal cardiac and renal functions. This subgroup of patients had high NT-proBNP levels ranging between 1115 and 60417 pg/mL, much higher than the 95th percentile NT-proBNP level in reference children (350 pg/mL).3 The high NT-proBNP levels in this small group of patients suggest that factors other than cardiac dysfunction may cause elevation of the peptide levels in patients with sepsis.

What is the origin of NT-proBNP in patients with shock? The elevated peptide levels may be a result of increased production, decreased clearance, or both. The peptide may be of cardiac origin or may be secreted by other tissues. One possibility is that the cardiac compromise was not apparent by echocardiography, because diastolic function was not assessed in this study. Sepsis and septic shock are states associated with high cardiac output, and therapy includes administration of fluids. It is possible that cardiac distension occurred, with preserved systolic function causing elevation of BNP secretion. Another possible cause for cardiac secretion of BNP is stress hormones, known to be elevated in a state of shock and to induce BNP synthesis and secretion. Proinflammatory cytokines have been reported to induce BNP synthesis11,12 and probably stimulate the peptide release in a state of sepsis. Other factors or tissues may be responsible for the elevated NT-proBNP levels. One of the suggested candidates is the kidney. High levels of BNP and NT-proBNP were reported in adults with renal failure.13,14 The reason for this phenomenon is not completely understood. It is possible that in this condition there is slower elimination of the peptide. Others have suggested subtle cardiac impairments in patients with renal disease. Patients with chronic renal failure were excluded from this study. However, we have found excessive elevation of NT-proBNP levels in acutely ill children with chronic renal failure. The finding of high NT-proBNP levels in patients with sepsis and normal left ventricular and renal function suggests that a factor or factors other than the heart and kidney are responsible for the elevated peptide levels in patients with sepsis. A significant limitation of this study was the small number of patients. Larger studies are needed to confirm our findings.


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We report elevated levels of NT-proBNP in infants and children with sepsis. Patients with similar hemodynamic status resulting from heart disease had significantly higher NT-proBNP levels. The overlap between NT-proBNP levels in sepsis and acute LVD precludes the use of the peptide's level as a sole means to differentiate between these conditions. However, in the setting of the ICU, patients with excessive elevation of NT-proBNP levels should be suspected of having acute LVD.


   ACKNOWLEDGMENTS
 
We thank Sherri Aharoni for technical and secretarial support and Hana Amsalem and the Shaare Zedek Endocrinology Laboratory staff for superb technical support.


   FOOTNOTES
 
Accepted May 23, 2006.

Address correspondence to Amiram Nir, MD, Shaare Zedek Medical Center, Pediatric Cardiology Unit, PO Box 3235, Jerusalem 91031, Israel. E-mail: amiramn{at}md.huji.ac.il

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Baugman KL. B-type natriuretic peptide: a window to the heart. N Engl J Med. 2002;347 :158 –159[Free Full Text]
  2. Masson S, Vago T, Baldi G, et al. Comparative measurement of N-terminal pro-brain natriuretic peptide and brain natriuretic peptide in ambulatory patients with heart failure. Clin Chem Lab Med. 2002;40 :761 –763[CrossRef][ISI][Medline]
  3. Nir A, Bar-Oz B, Perles Z, Brooks R, Korach A, Rein AJ. N-terminal pro-B-type natriuretic peptide: reference plasma levels from birth to adolescence—elevated levels at birth and in heart diseases. Acta Paediatr. 2004;93 :603 –607[CrossRef][ISI][Medline]
  4. Hoffmann U, Brueckmann M, Bertsch T, et al. Increased plasma levels of NT-proANP and NT-proBNP as markers of cardiac dysfunction in septic patients. Clin Lab. 2005;51 :373 –379[ISI][Medline]
  5. Brueckmann M, Huhle G, Lang S, et al. Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis. Circulation. 2005;112 :527 –534[Abstract/Free Full Text]
  6. Jacobs RF, Darville T. Bacteremia, sepsis and septic shock. In: Rudolph CB, Rudolph AM, eds. Rudolph's Pediatrics. 21st ed. New York, NY: McGraw-Hill; 2002:896–900
  7. Mir TS, Marohn S, Laer S, Eiselt M, Grollmus O, Weil J. Plasma concentrations of N-terminal pro-brain natriuretic peptide in control children from the neonatal to adolescent period and in children with congestive heart failure. Pediatrics. 2002;110(6) . Available at: www.pediatrics.org/cgi/content/full/110/6/e76
  8. Hammerer-Lercher A, Neubauer E, Muller S, et al. Head-to-head comparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction. Clin Chim Acta. 2001;310 :193 –197[CrossRef][ISI][Medline]
  9. Witthaut R, Busch C, Fraunberger P, et al. Plasma atrial natriuretic peptide and brain natriuretic peptide are increased in septic shock: impact of interleukin-6 and sepsis-associated left ventricular dysfunction. Intensive Care Med. 2003;29 :1696 –1702[CrossRef][ISI][Medline]
  10. Charpentier J, Luyt C, Fulla Y, et al. Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med. 2004;32 :660 –665[CrossRef][ISI][Medline]
  11. Ma KK, Ogawa T, de Bold AJ. Selective upregulation of cardiac brain natriuretic peptide at the transcriptional and translational levels by pro-inflammatory cytokines and by conditioned medium derived from mixed lymphocyte reactions via p38 MAP kinase. J Mol Cell Cardiol. 2004;36 :505 –513[CrossRef][ISI][Medline]
  12. Clerico A, Recchia FA, Passino C, et al. Cardiac endocrine function is an essential component of the homeostatic regulation network: physiological and clinical implications. Am J Physiol Heart Circ Physiol. 2006;290 :H17 –H29[Abstract/Free Full Text]
  13. Vesely DL. Natriuretic peptides and acute renal failure. Am J Physiol Renal Physiol. 2003;285 :F167 –F177[Abstract/Free Full Text]
  14. Luchner A, Hengstenberg C, Lowel H, Riegger GA, Schunkert H, Holmer S. Effect of compensated renal dysfunction on approved heart failure markers: direct comparison of brain natriuretic peptide (BNP) and N-terminal pro-BNP. Hypertension. 2005;46 :118 –123[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



This article has been cited by other articles:


Home page
 Arch. Dis. Child. Fetal Neonatal Ed.Home page
I Farombi-Oghuvbu, T Matthews, P D Mayne, H Guerin, and J D Corcoran
N-terminal pro-B-type natriuretic peptide: a measure of significant patent ductus arteriosus
Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2008; 93(4): F257 - F260.
[Abstract] [Full Text] [PDF]

Home page
 Arch. Dis. Child. Fetal Neonatal Ed.Home page
A. El-Khuffash and E. J Molloy
Are B-type natriuretic peptide (BNP) and N-terminal-pro-BNP useful in neonates?
Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2007; 92(4): F320 - F324.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fried, I.
Right arrow Articles by Nir, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fried, I.
Right arrow Articles by Nir, A.
Related Collections
Right arrow Heart & Blood Vessels