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(Circulation. 2006;113:e25.)
© 2006 American Heart Association, Inc.

Correspondence

Letter Regarding Article by Brueckmann et al, "Prognostic Value of Plasma N-Terminal Pro-Brain Natriuretic Peptide in Patients With Severe Sepsis"

James L. Januzzi, MD

Divisions of Cardiology, Massachusetts General Hospital, Boston, Mass

B. Taylor Thompson, MD

Divisions of Pulmonary/Critical Care Medicine, Massachusetts General Hospital, Boston, Mass

Roderick Tung, MD

Division of Cardiology, Cedars Sinai Medical Center, Los Angeles, Calif

To the Editor:

We read with interest the work by Brueckmann et al¹ regarding the association between elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) and mortality in patients with bacterial sepsis. We previously published a similar relationship between BNP and mortality in subjects with shock of various types² and found results of BNP testing to be strongly related to mortality in shock independently of measures of disease severity (Acute Physiology And Chronic Health Evaluation [APACHE] II scoring) or cardiac hemodynamics and filling pressures.

In the study by Brueckmann and colleagues, other than serum creatinine measurement, it appears that measures of disease severity such as APACHE II scoring were not included in the development of their Cox regression model. Was NT-proBNP a significant predictor of death in the presence of APACHE II scores? In addition, we note that 35% of subjects in their study demonstrated an ejection fraction of <50% and that these subjects accounted for the majority of those dying in the study. Presumably, most marked elevations of NT-proBNP would have been observed in those with impaired LV function. Was the presence of left ventricular dysfunction considered in the development of the Cox model?

Finally, the authors refer to NT-proBNP values in terms of pmol/L. This is not likely to be appropriate because it is not known whether the assays for NT-proBNP are entirely specific for the 76–amino acid NT-proBNP moiety, with a high likelihood that small amounts of intact proBNP₁₀₈ (the intracellular precleavage precursor to BNP and NT-proBNP) are detected and measured by these assays. Given the differences in molecular weight between NT-proBNP and proBNP₁₀₈, reporting results as a function of molarity is not likely to be accurate; per recent consensus,³ the more appropriate method is to report in pg/mL (which results in NT-proBNP values 8.457 times higher than pmol/L).

	References

Top References References

 

1. 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: 527–534.[Abstract/Free Full Text]
   
2. Tung RH, Garcia C, Morss AM, Pino RM, Fifer MA, Thompson BT, Lewandrowski K, Lee-Lewandrowski E, Januzzi JL. Utility of B-type natriuretic peptide for the evaluation of intensive care unit shock. Crit Care Med. 2004; 32: 1643–1647.[CrossRef][Medline] [Order article via Infotrieve]
   
3. Christenson R, Apple F, Cannon C, Francis G, Jesse R, Morrow D, Newby LKR, Storrow JA, Tang HW, Wu A. National Association of Clinical Biochemistry laboratory medicine practice guidelines: biomarkers of acute coronary syndrome and heart failure. Available at: http://www.nacb.org/lmpg/card_biomarkers_LMPG_draft_PDF.stm. Accessed February 24, 2004.
   

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Response

Martina Brueckmann, MD; Guenter Huhle, MD; Siegfried Lang, PhD; Karl K. Haase, MD; Christel Weiß, PhD; Jens J. Kaden, MD; Martin Borggrefe, MD; Ursula Hoffmann, MD

Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany

Thomas Bertsch, MD

Institute of Clinical Chemistry and Laboratory Medicine, Clinic Nuremberg, Nuremberg, Germany

Christian Putensen, MD

Department of Anesthesiology, University Hospital, Bonn, Germany

We appreciate the interest of Dr Januzzi and colleagues in our article.¹ Inspired by their comments, we performed additional statistical evaluation, including Acute Physiology And Chronic Health Evaluation (APACHE) II scores in the Cox proportional-hazards regression model. Similar to the study of Tung et al,² N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in our study were independent predictors of mortality even after controlling for disease severity. Because of the limited number of patients, the Cox regression should not be overcharged by the inclusion of too many variables. Hence, we did not add cardiac index, left ventricular stroke work index, and ejection fraction to the model. Statistical reevaluation of our data revealed that APACHE II scores do not add significantly to the prediction of mortality in the presence of NT-proBNP.

We agree that several different fragments of the proBNP precursor may be present in human circulation in as-yet-unknown amounts.³ Fragments 8 to 29, 31 to 57, and 1 to 76 and the whole proBNP_{1– 108} precursor have been described. For this study a competitive ELISA with an antibody directed against amino acids 8 to 29 of the human BNP precursor from Biozol-Biomedica was used, with a high likelihood of detecting split products and the intact proBNP_{1– 108} precursor. Calibration of this assay was performed with synthetic peptide_8–29 (molecular weight, 2399g/mol), resulting in the following conversion factor: 1 pmol/L=2.399 pg/mL. The usefulness of this assay has been confirmed by several studies.⁴ Stating values in pg/mL or pmol/L depends on the assay type and the epitope actually detected. Although the National Academy of Clinical Biochemistry consensus concerning the units of natriuretic peptides is just in the state of recommendation, we are in accordance with Dr Januzzi to report uniformly in pg/mL to make results more comparable in future trials.

	References

Top References References

 

1. 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: 527–534.[Abstract/Free Full Text]
   
2. Tung RH, Garcia C, Morss AM, Pino RM, Fifer MA, Thompson BT, Lewandrowski K, Lee-Lewandrowski E, Januzzi JL. Utility of B-type natriuretic peptide for the evaluation of intensive care unit shock. Crit Care Med. 2004; 32: 1643–1647.[CrossRef][Medline] [Order article via Infotrieve]
   
3. Panteghini M, Clerico A. Understanding the clinical biochemistry of N-terminal pro-B-type natriuretic peptide: the prerequisite for its optimal clinical use. Clin Lab. 2004; 50: 325–331.[Medline] [Order article via Infotrieve]
   
4. Mueller T, Gegenhuber A, Poelz W, Haltmayer M. Comparison of the Biomedica NT-proBNP enzyme immunoassay and the Roche NT-proBNP chemiluminescence immunoassay: implications for the prediction of symptomatic and asymptomatic structural heart disease. Clin Chem. 2003; 49: 976–979.[Free Full Text]
   

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Issue Highlights
Circulation 2006 113: 177. [Full Text]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Januzzi, J. L. Articles by Putensen, C. Search for Related Content PubMed PubMed Citation Articles by Januzzi, J. L. Articles by Putensen, C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Sepsis Related Collections Other diagnostic testing Related Article