Continuous, complete and comparable NT-proBNP reference ranges in healthy children

Palm J, Hoffmann G, Klawonn F, Tutarel O, Palm H, Holdenrieder S, Ewert P.

Clin Chem Lab Med. 2020 Apr 18. pii: /j/cclm.ahead-of-print/cclm-2019-1185/cclm-2019-1185.xml. doi: 10.1515/cclm-2019-1185. [Epub ahead of print]

PMID: 32305952

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Background NT-proBNP is one of the most important biomarkers for the diagnosis and risk assessment of heart failure in adults. Age- and gender-independent reference intervals (RIs) have been reported. In contrast, RIs in children are strongly age-dependent, do not exist for all ages and reveal a right-skewed distribution. Accordingly, no common Z-score can be formed and a cross-age interpretive method, so far, is missing. Methods Within the paper on hand, new evaluation techniques are applied to already published NT-proBNP study results and additionally to newly gained data. Upper limits (ULs), lower limits (LLs) and 50th percentiles are tested for power-like behavior as a function of age using linear regression analysis. Functions for continuous RIs are derived and reference limits are calculated on a per day basis. A corresponding Zlog formula is deduced and its usefulness is stated in two clinical examples. Results The power-like behavior of NT-proBNP concentration from birth to 18 years is demonstrated. With age in days t and measured NT-proBNP value x in pg/mL, an age-specific Zlog value may directly be calculated using the equation: ZlogNT-proBNP=log x+0.512⋅log t-3.4171.489+0.014⋅log t⋅3.92 ${\rm{Zlo}}{{\rm{g}}_{{\rm{NT – proBNP}}}} = {{\log \;x + 0.512 \cdot \log \;t – 3.417} \over {1.489 + 0.014 \cdot \log \;t}} \cdot 3.92$ Conclusions Using formulas for UL and LL, continuous RIs from 0 to 18 years may be obtained. Continuity corresponds to physiological changes in the body much better than discrete RIs. With the advent of an NT-proBNP-specific Zlog value, a cross-age Z-score equivalent is providing an easy interpretation aid in everyday pediatric practice. This new approach allows to identify clinical worsening much better, sooner and more clearly than previous absolute values.