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N-terminal pro-brain natriuretic peptide (NT-pro-BNP)
Date of SC final approval:
About the Measure
Domain:
Measure:
Definition:
Purpose:
Sickle Cell Disease: Cardiovascular, Pulmonary, and Renal
N-terminal pro-brain natriuretic peptide (NT-pro-BNP)
A bioassay to determine an individual’s level of N-terminal pro-brain natriuretic peptide
(NT-pro-BNP).
N-terminal pro-brain natriuretic peptide (NT-pro-BNP) is released from the right or left
ventricle of the heart when it is under pressure stress. Levels of NT-pro-BNP can be
used as a screening tool to evaluate an individual’s left ventricular ejection fraction
(LVEF). Studies have shown that left ventricular systolic dysfunction is associated with
chronic heart failure. Additionally, levels of NT-pro-BNP can be elevated in patients
with Sickle Cell Disease.
About the Protocol
Description of
Protocol:
Selection
Rationale:
Specific
Instructions:
This protocol provides instructions for drawing, processing and storing blood
according to the National Health and Nutrition Examination Survey (NHANES)
methods. As there are many comparable assays for ascertaining levels of N-terminalpro-brain natriuretic peptide (NT-pro-BNP), the protocol also provides basic guidelines
to aid comparability among different studies.
The Sickle Cell Disease Cardiovascular, Pulmonary, and Renal Working Group
selected NT-pro-BNP measurement because it is a validated, specific, low-burden,
non-invasive alternative to echocardiography for differentiating patients with
ventricular dysfunction. Additionally, this assay does not require sample extraction
and there is no detectable cross reactivity with atrial natriuretic peptide (ANP), Nterminal pro-atrial natriuretic peptide (NT-proANP), brain natriuretic peptide (BNP), or
urodilatin.
 The NHANES instructions for drawing, processing and storing blood provide a
standard methodology used successfully for many years to ensure comparable
results across study sites. However, the Sickle Cell Disease Working Group 1
(Cardiovascular, Pulmonary, and Renal) notes that certain aspects (e.g.,
exclusion criteria) of the NHANES protocol are study specific and might not be
applicable to all types of studies (e.g., sickle cell disease).

Collection of blood samples for the measurement of analytes requires a
general determination of whether to use serum or plasma for the assay and
also a determination of the type of collection tube to be obtained. For example,
if serum is to be used a determination needs to be made as to whether red top
or serum gel separator collection tubes are used. While comparable values are
obtained for many analytes from either serum or plasma, there may be
situations where differences are more pronounced and serum or plasma
specific norms will be needed for references. The protocol presented here
uses red top/serum separator tubes. At times it may be possible to collect
both, but other considerations such as participant burden may be the deciding
factor. It is important to match assay type with sample type. Some automated
devices may preclude the use of serum, for example, while others may be
optimized for it. Investigators should choose methods of collection that match
the methods of analysis. This will best be done by communicating with the
laboratory where the proposed assays will be performed. They will become an
important partner with you in assuring that there is compatibility from collection
Version 10 – 10/21/09
N-terminal pro-brain natriuretic peptide (NT-pro-BNP)
Date of SC final approval:
to assays to interpretation and reporting of levels and results.
Protocol Text:
Summary of the N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Assay
The following is a summary version of the full National Health and Nutrition
Examination Survey 2011-2012 protocol.
Exclusion Criteria
Persons will be excluded from this component if they:
• Report that they have hemophilia; or
• Report that they have received cancer chemotherapy in the last 4 weeks
SP = Sample Person.
1. Do you have hemophilia?
1[]
2[]
7[]
9[]
Yes
No
Refused
Don’t Know
If the SP answers, "Yes," the SP is excluded from the blood draw.
If SP answer "No" or "Don’t Know," blood is drawn from the SP.
2. Have you received cancer chemotherapy in the past four weeks or do you
anticipate such therapy in the next four weeks?
1 [ ] Yes
2 [ ] No
7 [ ] Refused
9 [ ] Don’t Know
If the SP answers, "Yes," the SP is excluded from the blood draw.
If SP answer "No" or "Don’t Know," blood is drawn from the SP.
Venipuncture Procedures
Editor’s Note: Please review chapter 4 of the Laboratory Procedures Manual from the
2011-2012 National Health and Nutrition Examination Survey for a full description of
Phlebotomy procedures. This manual is posted here, and is also available at the
NHANES website: 2011-2012 NHANES Laboratory Procedures Manual
Venipuncture should generally be performed using the median cubital, cephalic, or
basilic veins in the left arm unless this arm is unsuitable. If the veins in the left arm are
unsuitable, look for suitable veins on the right arm. If the veins in the antecubital
space on both arms are not suitable, then look for veins in the forearm or dorsal side
of the hand on the left arm/hand and then the right arm/hand.
Version 10 – 10/21/09
N-terminal pro-brain natriuretic peptide (NT-pro-BNP)
Date of SC final approval:
Recording the Results of the Venipuncture Procedure
Immediately after completing the venipuncture, record the results of the blood draw,
the reasons for a tube not being drawn according to the protocol, and any comments
about the venipuncture.
Blood Processing
Please review chapter 8 of the Laboratory Procedures Manual from the National
Health and Nutrition Examination Survey 2011-2012 for a full description of Blood
Processing procedures: 2011-2012 NHANES Laboratory Procedures Manual
•
•
•
Allow the blood to clot by setting aside for 30 to 45 minutes at room
temperature. Do not clot for more than an hour.
Centrifuge the tube at room temperature to separate the serum and aliquot
into an appropriate storage tube.
Determine if the serum is hemolyzed, turbid, lipemic, or icteric. If so, enter a
comment to describe the serum.
Laboratory Assay for NT-proBNP
NT-proBNP can be measured using a two-step sandwich enzyme-linked
immunosorbent assay (ELISA)—in streptavidin coated microtitre plates. The Working
Groups notes that there are a number of different reagents and instruments which are
appropriate to measure the concentration of NT-proBNP. Once an assay is chosen for
a particular study, the Working Group recommends that no changes in the protocol be
made over the course of the study. To aid comparability, the Working Group
recommends that the investigator record the make and manufacturer of equipment
used and the repeatability and coefficients of variation for the assay.
Participant:
Source:
Language of
Source:
Personnel and
Training Required:
Reference Ranges
“In patients with an LVEF of > 50%, 85% of subjects had an NT-proBNP value below
357 pmol/l (1n (357) = 5.9). This value was used as the upper normal limit in the
analyses of sensitivity and specificity. It should be stressed that 357 pmol/l is not a
true normal value but a cut off value derived from the present hospital inpatient
population.”
Adults
Centers for Disease Control and Prevention (CDC). Nutritional Biomarkers Branch
(NBB). Division of Laboratory Sciences. National Center for Environmental Health.
National Health and Nutrition Examination Survey Questionnaire. Laboratory
Procedures Manual. Hyattsville, MD: U.S. Department of Health and Human Services,
Centers for Disease Control and Prevention, 2011-2012.
Bay, M., Kirk, V., Parner, J., Hassager, C., Nielsen, H., Krogsgaard, K., Trawinski, J.,
Boesgaard, S., & Aldershvile, J. (2003). NT-proBNP: a new diagnostic screening tool
to differentiate between patients with normal and reduced left ventricular systolic
function. Heart; 89:150–154.
English
A phlebotomist, nursing staff, or other health care professional who is trained to draw
blood and laboratory staff who are trained to perform this assay.
Version 10 – 10/21/09
N-terminal pro-brain natriuretic peptide (NT-pro-BNP)
Date of SC final approval:
Equipment Needs:
Phlebotomy supplies, centrifuge for serum separation, freezer for sample storage is
required.
Protocol Type:
Bioassay
Requirements:
Requirements Category
Common Data
Elements:
General
References:
Required (Yes/No):
Major equipment
No
Specialized training
No
Specialized requirements for biospecimen
collection
Average time of greater than 15 minutes in an
unaffected individual
TBD by PhenX Team
No
No
Machado, R. F., Hildesheim, M., Mendelsohn, L., Remaley, A. T., Kato, G. J., &
Gladwin, M. T. (2011). NT-pro brain natriuretic peptide levels and the risk of death in
the cooperative study of sickle cell disease British Journal of Haematology Volume
154, issue 4, pp 512–520.
Machado, R. F., Anthi, A., Steinberg, M. H., Bonds, D., Sachdev, V., Kato, G. J.,
Taveira-DaSilva, A. M., Ballas, S. K., Blackwelder, W., Xu, X., Hunter, L., Barton, B.,
Waclawiw, M., Castro,O., Gladwin, M. T. for the MSH Investigators (2006). N-Terminal
Pro-Brain Natriuretic Peptide Levels and Risk of Death in Sickle Cell Disease JAMA
296 (3):310-318. doi:10.1001/jama.296.3.310.
Karl, J., Borgya, A., Gallusser, A., Huber, E., Krueger, K., Rollinger, W. & Schenk, J.
(1999). Development of a novel, N-Terminal-proBNP (NT-proBNP) assay with a low
detection limit Scand JClin Lab Invest 1999; 59(Suppl230):177-181.
Additional Information About the Measure
Essential Data:
Current Age, Race, Ethnicity
Related PhenX
Measures:
Derived Variables:
Keywords/Related
Concepts:
Heart Valve Function, Pulmonary Hypertension, Blood Pressure
None
N-terminal pro-brain natriuretic peptide, NT-proBNP, Left Ventricular Ejection
Fraction, LVEF, Sickle Cell Disease, SCD, Chronic Heart Failure, Pulmonary
hypertension, PH, Biomarkers, Immunoassay
Version 10 – 10/21/09