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Natriuretic peptide testing for risk stratification of critically ill patients

An article from the e-journal of the ESC Council for Cardiology Practice

Natriuretic peptide testing identifies critically ill patients at higher risk of mortality. Brain natriuretic peptide (BNP) and amino-terminal pro-BNP (NT-proBNP) may serve as useful biomarkers to predict survival in intensive care unit patients suffering either from cardiac or septic shock. Moreover, these biomarkers may provide decision support for the application of further invasive methods for hemodynamic monitoring.

1. Role of natriuretic peptides in the diagnosis of heart failure

B-type natriuretic peptide (BNP) and amino-terminal pro-BNP (NT-proBNP) are promising cardiac biomarkers for evaluating acute heart failure (1).
Elevated serum levels have been described in both left ventricular systolic and diastolic dysfunction as well as in right ventricular pressure overload states, such as pulmonary embolism and pulmonary hypertension. Both biochemical markers appear to be useful in distinguishing between dyspnea due to heart failure or due to other causes, especially of pulmonary origin.

For clinicians a rapid measurement of natriuretic peptides in the emergency room makes it easier both to establish or to ‘rule out’ the initial diagnosis of heart failure (1,2). Increased levels of atrial natriuretic peptide (ANP) and BNP have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease.

2. Role of natriuretic peptides in critically ill patients

Recently, the role of these biomarkers has been intensively studied in critically ill patients suffering from various forms of shock including cardiac and septic shock. Patients with shock in the intensive care unit (ICU) usually have a high risk of mortality.

One method in evaluating shock patients is invasive hemodynamic monitoring with pulmonary artery catheterisation (PAC). However, despite almost 20 years of randomised clinical trials a clear benefit leading to improved survival from the use of PAC has not been proven.

Non-invasive methods for estimating hemodynamics and prognosis in intensive care unit patients are urgently needed. Several studies have demonstrated that levels of the “cardiac hormones” BNP and NT proBNP are increased in patients with cardiac dysfunction arising from sepsis or septic shock (3-5). Moreover, it has been shown that septic patients with elevated  NT-pro-BNP levels were about four times more likely to die within 28 days than patients with lower values (5).

Therefore, NT-proBNP has been suggested to serve as useful biomarker to predict survival in patients with severe sepsis. Although elevated levels of NT-proBNP do not necessarily correlate with high filling pressures among patients with ICU shock, a marked elevation in NT-proBNP is strongly associated with ICU death (6). Low NT-proBNP values in patients with ICU shock identifies those at lower risk of death, and may be useful in excluding the need for pulmonary artery catheter placement in such patients. Levels below 1200pg/ml have an excellent negative predictive value of 92% for cardiogenic shock waiving the need for additional invasive diagnostic procedures (6).

There has been a broad discussion about the usefulness of PAC in ICU patients. The neutrality of PAC for clinical outcomes of critically ill patients may result from the absence of effective evidence-based treatment regimens according to PAC information across the broad spectrum of critically ill patients. Elevated levels of natriuretic peptides, however, might be easier to interpret and undoubtedly indicate a higher risk of mortality of a given critically ill patient.

3. Mechanisms contributing to elevated natriuretic peptide levels in ICU-patients

Left ventricular stretch and elevations of end-diastolic pressure and volume regulate the release of natriuretic peptides from the cardiac ventricle in acute heart failure patients. In critically ill patients, especially in those with an infectious origin of their disease, several other mechanisms account for increased natriuretic peptide levels and for the observed lack of association with cardiac filling pressures and hemodynamics: Lipopolysaccharide and proinflammatory cytokines up-regulate the transcription of the gene encoding for BNP in cardiomyocytes. For example, a correlation between the proinflammatory cytokine interleukin-6 (IL-6) and natriuretic peptides was found (3).

Thus, plasma levels of natriuretic peptides are not only affected by left ventricular dysfunction, but also by inflammatory cytokines corresponding to the magnitude of infection within ICU patients. However, further studies evaluating the precise mechanisms for enhanced natriuretic peptide secretion in critically ill patients are still needed.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.



Elevated levels of BNP or NT-proBNP characterise critically ill patients suffering not only from cardiac shock, but also identifies those with reversible left ventricular dysfunction due to severe sepsis and septic shock. The measurement of natriuretic peptides in critically ill patients may help to identify candidates at higher risk of mortality. Moreover, it may provide promising decision support for the application of further treatment regimens and diagnostic procedures including invasive hemodynamic measurements in critically ill patients.

Whether measurement of NT-proBNP or BNP is valuable in the clinical course of sepsis or for guiding therapy afterwards in the private cardiologist's office, has not been examined yet within a clinical trial. As for chronic heart failure, guiding therapy according to BNP-levels may be useful, but further clinical trial data are needed to prove this.


1. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA; for the Breathing Not Properly Multinational Study Investigators. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. New Engl J Med 2002;347:161-7.

2. Mueller C, Scholer A, Laule-Kilian K, Martina B, Schindler C, Buser P, Pfisterer M, Perruchoud AP. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med. 2004; 350:647-54.

3. Witthaut R, Busch C, Fraunberger P, Walli A, Seidel D, Pilz G, Stuttmann R, Speichermann N, Verner L, Werdan K. 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;29:1696-702.
4. Charpentier J, Luyt CE, Fulla Y, Vinsonneau C, Cariou A, Grabar S, Dhainaut JF, Mira JP, Chiche JD. Brain natriuretic peptide: A marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med. 2004 ;32:660-5.

5. Brueckmann M, Huhle G, Lang S, Haase KK, Bertsch T, Weiss C, Kaden JJ, Putensen C, Borggrefe M, Hoffmann U. Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis. Circulation 2005;112:527-34.

6. Januzzi JL, Morss A, Tung R, Pino R, Fifer MA, Thompson BT, Lee-Lewandrowski E. Natriuretic peptide testing for the evaluation of critically ill patients with shock in the intensive care unit: a prospective cohort study. Crit Care 2006;10 (1):R37.



Vol5 N°14

Notes to editor

Prof. *M. Borggrefe
Mannheim, Germany
*Chair of the International Affairs & National Societies Committee

Martina Brueckmann MD, First Department of Medicine, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany, Phone and FAX: 0049-621-383-2875

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.