Focus On: Brain Natriuretic Peptide
By Lisa Rapoport, MD and Alan M. Kumar, MD
After reading this article, the physician should be able to:
- Understand what brain natriuretic peptide (BNP) is and the difference between types of BNP measured.
- Use and interpret BNP in the emergency setting.
- Understand the modifying factors that affect interpretation.
Brain natriuretic peptide, or BNP, is a natriuretic hormone that was initially identified in the brain but is also present in the heart, particularly the ventricle. The plasma concentration of this hormone rises greatly during times of higher ventricular filling pressures, thus allowing it to be used in the diagnosis and management of congestive heart failure.
Over the last decade, numerous studies have validated its use to aid in the diagnosis of acute heart failure in the emergency department. It is a relatively new tool that busy emergency physicians can use to augment their clinical skills in the evaluation of patients with dyspnea. However, emergency physicians must understand the benefits and limitations of this test in order to use it effectively and appropriately.
What Is BNP?
BNP is synthesized in myocytes as the larger, inactive molecule proBNP. It is subsequently cleaved to produce the active hormone BNP and its inactive counterpart, the fragment NT-proBNP. BNP is rapidly secreted by the ventricles in response to myocardial wall stress and reflects the degree of left ventricular dysfunction and volume overload. Its effects are to promote the excretion of sodium and water by the kidneys (natriuresis and diuresis), to relax vascular smooth muscle cells, to improve myocyte relaxation during diastole, and to decrease myocardial fibrosis and remodeling.
BNP is cleared by the kidneys and also through enzymatic degradation in the kidneys, vascular endothelium, lungs, and heart. NT-proBNP is cleared predominately by the kidneys. The half-life of BNP is 23 minutes, and the NT-proBNP fragment has a half-life of 60-120 minutes. Because of this short time frame, the time needed to reflect meaningful changes in hemodynamic status is approximately 2 hours for BNP and 12 hours for NT-proBNP.
How to Use BNP
The research that elucidated the physiology and clinical applications of BNP has been around for more than 20 years, but it was the availability of a rapid automated immunoassay in 2000 that led to wider adoption of BNP as a clinically relevant lab study in symptomatic patients.
In normal patients without cardiac disease, plasma concentrations of BNP and NT-proBNP are similar. In patients with left ventricular dysfunction, levels of NT-proBNP rise fourfold higher than BNP. Several published studies demonstrate that BNP and NT-proBNP have the same diagnostic accuracy, so it is acceptable to use either one.
BNP elevations are accurate in diagnosing diastolic dysfunction with the same effectiveness as in systolic dysfunction. Asymptomatic left ventricular dysfunction alone leads to higher baseline BNP levels. However, as a general guideline, acute heart failure is unlikely with a BNP less than 100 pg/dL or NT-proBNP less than 300 pg/dL, and acute heart failure is likely if BNP is greater than 500 pg/dL or NT-proBNP is greater than 1,000 pg/dL. These cutoff points, noticeably wide, have been chosen to optimize both sensitivity and specificity.
At these levels, the sensitivity ranges between 90% and 98%, with a negative likelihood ratio of 0.1 (a negative likelihood ratio is the probability of a negative test given a negative result, or the ratio of false negatives to true negatives). The specificity is approximately 86%, with a positive likelihood ratio of 6 (the ratio of true positives to false positives). Yet a negative likelihood ratio of 0.1 implies that 10 patients out of 100 who are sent home without the diagnosis of acute heart failure will actually have it, which may have harmful sequelae for obvious reasons.
In addition, given that a test's accuracy parameters are affected by the prevalence of disease in a population, the emergency physician's clinical judgment will always come into play when evaluating acute dyspnea in the emergency department. Indeed, the large BNP trials have concluded that an emergency physician's clinical assessment in addition to BNP measurement is better than either used alone.
The corollary to this is that even with a negative BNP level, if the clinician's pre-test probability (judgment) is high enough, a negative BNP is not enough to rule out CHF.
It should also be noted that different commercial assays give different results and thus have different cutoff levels; for this reason, it is important to be familiar with the specifics of which assay is used by each hospital. Furthermore, these variances can make comparison between clinical studies using different assays difficult to interpret.
BNP and NT-proBNP are also elevated in patients with renal impairment. Although plasma BNP is primarily cleared by enzymatic degradation from multiple sources, research has proven that the glomerular filtration rate is inversely related to BNP concentrations. Therefore, the clinically relevant values of BNP in patients with renal insufficiency are different from those in patients with normal renal function.
In addition, NT-proBNP is primarily cleared by the kidneys, so its plasma concentrations are greatly elevated by renal failure. It is very difficult to interpret their levels in the setting of renal insufficiency, and in many of the larger clinical trials, subjects with elevated creatinines were not included in data sets.
Cutoff levels of 200 and 1,200 have been proposed for negative BNP and NT-proBNP levels, respectively, in patients with creatinine clearances less than 60 mL/min per 1.73 m2. Yet it is the authors' understanding that these cutoffs are not widely used, and BNP levels in renally impaired patients are best interpreted when compared to a baseline or a trend, not in a single ED measurement. BNP and NT-proBNP levels are elevated in older patients and in women more than men. A suggested guide is that the BNP level in a normal person should be less than half their chronologic age.
On the other hand, BNP and NT-proBNP are lowered in obese patients, prompting some investigators to suggest that lower levels of BNP in obese patients may contribute to the link between obesity and hypertension-related disorders. The optimal reference range would be dependent on sex, age, and body mass index.
Other potential causes of elevated BNP levels include diastolic dysfunction, acute coronary syndromes (very sensitive but not specific), hypertension with LVH, valvular heart disease, atrial fibrillation, and pulmonary embolism, pulmonary hypertension, sepsis, COPD, or hyperthyroidism.
Alternative Applications of BNP
BNP and NT-proBNP levels also can be used in patients outside the acute decompensated heart failure population. Outpatient measurements of BNP have been used in chronic heart failure management and show promising outcome benefits. Although the half-lives of BNP and NT-proBNP are short, studies looking at serial measurements during the inpatient portion of patients' stays have resulted in conflicting data, and this practice is currently not recommended.
Natriuretic peptide levels also have been studied and used as predictors of mortality in populations of patients with heart failure or end-stage renal disease. In fact, the measurement of BNP and NT-proBNP has important prognostic importance in acute coronary syndromes. Patients with elevated natriuretic peptide levels after ACS have a significantly higher mortality than patients with normal levels. Specifically, elevated NT-proBNP levels after an MI have a higher correlation with death than any other marker studied, including C-reactive protein and troponin. However, data suggest that the use of BNP as a screening tool in asymptomatic or healthy populations is not particularly helpful, nor is it reliable as a marker of acute coronary syndromes.
A single BNP or NT-proBNP measurement is helpful in an emergency setting to help differentiate the cause of acute dyspnea. In fact, a single measurement of BNP in the emergency department is associated with greater diagnostic accuracy, and its use decreases time to discharge and cost of stay. If the BNP is very elevated, it helps to rule in acute heart failure syndrome. If the BNP is very low, it helps to rule out acute heart failure syndrome.
However, in between the two extremes is an intermediate zone that does not particularly weigh in either direction, and in these cases the clinician's judgment is paramount. Also, patients may present with multiple causes of dyspnea (pneumonia with an exacerbation of heart failure), and an elevated BNP does not rule out other causes of shortness of breath.n
- Brown et al. The Impact of B-type natriuretic peptide in addition to troponin-I, CKMB, and myoglobin on the risk stratification of emergency department chest pain patients with potential acute coronary syndromes. Annals of Emergency Medicine. 49(2):153-63.
- DiSomma et al. Decrease in NTproBNP plasma levels indicates clinical improvement of acute decompensated heart failure. American Journal Emergency Med. 25:335-9.
- Felker, Petersen, Mark. Natriuretic peptides in the diagnosis and management of heart failure. CMAJ. 175(6):611-7.
- Maisel et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 347(3):161-7.
- Mueller et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med. 350(7):647-54.
- Silvers et al. Clinical Policy: Critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Annals of Emergency Medicine. 49(5):627-69.
Dr. Lisa Rapoport is a third-year resident in the University of Chicago Emergency Medicine Residency. Dr. Alan M. Kumar is a clinical instructor in emergency medicine at the University of Chicago and Northwestern University, and practices emergency medicine at Lutheran General Hospital in Park Ridge, Ill. Medical Editor Dr. Robert C. Solomon is an attending emergency physician at Trinity Health System in Steubenville, Ohio, and clinical assistant professor of emergency medicine at the West Virginia School of Osteopathic Medicine.
In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards and American College of Emergency Physicians policy, contributors and editors must disclose to the program audience the existence of significant financial interests in or relationships with manufacturers of commercial products that might have a direct interest in the subject matter.
Dr. Rapoport, Dr. Kumar, and Dr. Solomon have disclosed that they have no financial, intellectual, or proprietary conflicts of interest regarding this educational activity.
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