Utility of point-of-care testing of natriuretic peptides (brain natriuretic peptide and n-terminal pro-brain natriuretic peptide) in the emergency department.

Rapid and accurate diagnosis of a patient with an acute disease is a challenge for emergency physicians. Natriuretic peptides have emerged as important tools for diagnosis, risk stratification and therapeutic decision making for some categories of emergency patients. Brain natriuretic peptide (BNP) is a member of a four natriuretic peptides family that shares a common 17-peptide ring structure. Atrial natriuretic peptide, C-natriuretic peptide (CNP), and D-type natriuretic peptide are the other natriuretic peptide, which share the same common 17-peptide ring structure. The N-terminal fragment of pro-BNP, N-terminal pro-brain natriuretic peptide (NT-proBNP) consists of 76 amino acids, which is biologically inert, while the active component BNP contains 32 amino acids. BNP and NT-proBNP are secreted in the plasma in equimolar quantities and are frequently used in the diagnosis of congestive heart failure, and distinguishing between patients with dyspnea of cardiac or pulmonary origin. Both natriuretic peptides have also been evaluated for use in the assessment and management of several other conditions including sepsis, cirrhosis of liver and renal failure. However, one should remember that the values of natriuretic peptides are affected by age and weight of the patients, and presence of several comorbidities such as chronic renal failure, type 2 diabetes mellitus, anemia, pulmonary embolism, and acute coronary syndrome. Values of these peptides also vary depending on the type of test used. The performance characteristics of these natriuretic peptides vary depending on the patients on whom they are used. Therefore determination of reference values for these peptides represents a challenge.

INTRODUCTION

In the year 2000, US- FDA approved brain natriuretic peptide (BNP) as an adjunct to diagnose heart failure. In the same year, Biosite Inc. (now Alere) introduced BNP as a point of assay for use in the emergency department (ED). American Heart Association/American College of Cardiology (AHA/ACC) Guidelines for diagnosis of heart failure endorse class IIa recommendation for use of natriuretic peptides.[1] BNP and N-terminal pro-brain natriuretic peptide (NT-proBNP) have generated excitement among emergency physicians not only in diagnosing heart failure but also in triage, and guide to treat and discharge of patients with heart failure. BNP and NT-proBNP are extremely helpful in risk stratification of patients in the ED with regard to the need of hospital admission or direct ED discharge. Natriuretic peptide levels help in improving patient care and reduction of morbidity and mortality. It also reduces the cost of treatment in the ED. In the past few years, considerable interest has generated regarding use of natriuretic peptides in patients with coronary artery disease (CAD), valvular heart diseases, severe sepsis and septic shock, renal failure, cirrhosis of liver, pulmonary conditions (e.g. chronic obstructive pulmonary disease, acute respiratory distress syndrome, pulmonary embolism, and pulmonary arterial hypertension), diabetes, and stroke. In subsequent sections, we will discuss physiology of natriuretic peptides, and their diagnostic and prognostic values in various emergency situations.

PHYSIOLOGY OF NATRIURETIC PEPTIDES

BNP was first described in 1988 by Sudoh et al. after isolation from porcine brain.[2] However, it was soon found to originate mainly from the ventricles. After stimulation of cardiomyocytes, pre-proBNP is released, which is cleaved into proBNP comprising of 108 amino acids. Pro-BNP is further cleaved in equal proportions into a 32-amino acid, biologically active peptide, the BNP, and a 76-amino acid long, biologically inactive peptide, the N-terminal fragment of pro-BNP (NT-proBNP). Both molecules are constantly released into circulation and can be detected in the blood. The main stimulus for increased BNP and NT-proBNP synthesis and secretion is myocardial wall stress. Furthermore, factors such as myocardial ischemia and endocrine (paracrine) modulation by other neurohormones and cytokines are also of importance.

In the systemic circulation, BNP mediates a variety of biological effects by interaction through natriuretic peptide receptor type A (NPR-A) causing intracellular cyclic guanosine monophosphate (cGMP) production. The physiological effects of BNP are manifold and comprise natriuresis/diuresis, peripheral vasodilatation, and inhibition of renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS) and endothelin.

BNP is cleared from plasma by binding to natriuretic peptide receptor type C (NPR-C) through proteolysis by neutral endopeptidases. NT-proBNP is mainly cleared by renal excretion. However, recent studies suggest that there might also be other important clearing mechanisms for NT-proBNP. The half-life of BNP is 20 min, whereas that of NT-proBNP is 120 min, which explains why NT-proBNP serum values are approximately six times higher than BNP values, even though both molecules are released in equimolar proportions.[3] Normally serum levels of BNP and NT-proBNP will be on higher side in elderly, females, and presence of ventricular hypertrophy or renal failure, but will be less than normal in obesity. So these variables should be taken into account while making judgment based on the levels of natriuretic peptides.

BNP AND NT-PROBNP AS POINT OF CARE TESTING IN ED

Both BNP and NT-proBNP can be measured on a point of care testing device within 15–20 min by a rapid fluorescene immunoassay (Alere Triage, San Diego). NT-proBNP can also be estimated by an electrochemiluminescent assay (Roche Diagnostic, Basel, Germany). Results of these points of care testing devices generally correlate well with the results of radioimmunoassay. Point of care testing is justifiable in the emergency settings where immediate decision has to be taken. It helps an emergency physician in triage, rapid diagnosis, and treatment of patients. Early decision-making saves time, cost of treatment, and also reduces overcrowding of EDs.

DIAGNOSTIC AND PROGNOSTIC VALUE OF BNP AND NT-PROBNP

Natriuretic peptides (BNP and NT-proBNP) measurements can be used as point of care testing in the ED to diagnose patients with several emergency conditions. These tests also help in prognosticating patients in the ED.

Acute undifferentiated dyspnea

Patients presenting with undifferentiated dyspnea are commonly encountered in the ED. The differential diagnosis of undifferentiated dyspnea includes congestive heart failure (CHF) (acute or acute-on-chronic), COPD, asthma, acute coronary syndrome (ACS), pneumonia, and pulmonary embolism. When clinicians remain uncertain of the cause of dyspnea in the ED, patients have longer hospital stay as well as increased morbidity and mortality.[4] Natriuretic peptides have demonstrated excellent sensitivity in diagnosing heart failure. Measurements of their levels using a point-of-care system improves accuracy of physician's decision-making, decreases errors, and significantly reduces the rate of clinical indecision on initial evaluation.[56] Meta-analysis of diagnostic accuracy studies yielded a negative likelihood ratio of 0.18 (95% confidence interval [CI] 0.13–0.23) for BNP and a negative likelihood ratio of 0.12 for NT-proBNP using age-related cut-off points to define abnormal levels.[78] Levels of BNP are less influenced by age than the levels of NT-proBNP; for this reason, interpretation of NT-proBNP values usually involves the use of age-stratified reference values.[9] Otherwise, use of BNP and NT-proBNP seems to be interchangeable, with no clinically meaningful differences in overall accuracy.[10]

There are numerous conditions like left ventricular hypertrophy, pulmonary hypertension, renal failure, ACS, atrial dysrhythmia, sepsis, pulmonary embolism, and lung cancer where natriuretic peptides level are on higher side.[11] American College of Emergency Physician (ACEP) recommends addition of a single BNP or NT-proBNP measurement to improve the diagnostic accuracy compared with standard clinical judgment alone in ED patients. It has given cut-off for BNP and NT-proBNP to “rule out” or “rule in” CHF [Table 1].[121314] Quantitative values of BNP and NT-proBNP are also helpful in risk stratification of patients with CHF. Patients with BNP level > 1730 pg/ml at presentation had an in- hospital mortality of more than three times than that of patients with BNP < 430 pg/ml. NT-proBNP levels of > 1000 pg/ml on ED presentation also suggest adverse prognosis.[815]

Table 1

Cut-off values for BNP and NT-proBNP for diagnosis of heart failure in patients presenting with dyspnea[121314]

Multiple studies have confirmed the usefulness of the determination of BNP and NT-proBNP levels in the plasma of patients with acute dyspnea [Table 2]. The Breathing Not Properly study, PRIDE study, ICON study, HFinCH study have all shown the diagnostic value of BNP and NT-proBNP.[61416171819] BASEL study and IMPROVE CHF study not only looked into the diagnosis and prognosis of heart failure but also emphasized the need of hospital admission and hospital stay in patients of heart failure based on the values of BNP and NT-proBNP.[202122] Val-HeFT and COPERNICUS studies indicated that chronic treatment with beta-blockers and blockers of the RAAS led to a reduction in levels of natriuretic peptides in patients of heart failure.[2324]

Table 2

Diagnostic performance of B-type natriuretic peptide (BNP) and NT-proBNP in CHF

BNP and NT-proBNP have also been shown to be important prognostic markers at the time of hospital admission in patients of heart failure [Table 3].[810252627] NT-proBNP-guided therapy in emergency is better than standard of care therapy (PROTECT Study). Target of NT-proBNP during treatment of CHF is to reduce it by ≥ 30% or keep it below 1000 pg/ml.[28]

Table 3

Prognostic values of B-type natriuretic peptide (BNP) and NT-proBNP in CHF

Coronary artery disease

BNP and NT-proBNP are mainly the biomarkers for heart failure. However, there has been growing evidence on the relevance of both markers in CAD. It is believed that the increase in BNP and NT-proBNP values in patients with CAD is due to left ventricular systolic or diastolic dysfunction caused by myocardial ischemia leading to an increased wall stress. Nevertheless some of the experimental studies suggest a direct release of natriuretic peptides from cardiomyocytes in response to myocardial ischemia independent of ventricular wall stress. In a patient with stable CAD, BNP levels have been shown to correlate linearly with number of coronary artery involvement [Table 4].[29]

Table 4

Relationship between BNP and Coronary artery involvement[29]

Various clinical trials (OPUS-TIMI 16, TACTICS-TIMI 18, FRISC II, GUSTO IV, and PRISM) have evaluated the prognostic value of BNP and NT-proBNP in patients presenting with non-ST elevation acute coronary syndromes (NSTE-ACS). These studies showed elevated values of BNP and NT-proBNP.[3031] Furthermore, both markers were highly predictive for an adverse outcome. Similar results were reported for the predictive value of BNP and NT-proBNP after ST elevation myocardial infarction (STEMI).[32] A rise of > 290 pg/ml after an index event of ACS represented a bad prognosis. Therapeutic benefit from early invasive strategy based on BNP and NT-proBNP is also proven by FRISC-II trial but further studies are needed to consolidate these findings.

NT-proBNP can be a good parameter for predicting the severity of coronary vessels involvement besides other diagnostic tools. In all patients with left ventricular ejection fraction less than 40%, plasma NT-proBNP level was higher than100 pg/ml, but there was no significant correlation between NT-proBNP and left ventricular end diastolic pressure (LVEDP) in patients with confirmed CAD.[33]

NT-proBNP levels were found to be elevated in patients with inducible myocardial ischemia versus those without (396 ± 80 pg/ml vs. 160 ± 101 pg/ml; P < 0.01), and this was closely linked to the extent of CAD (no CAD: 148 ± 29 pg/ml; one or two-vessel disease: 269 ± 50 pg/ml; three-vessel disease 624 ± 186 pg/ml; P < 0.01). In a multivariate analysis, NT-proBNP was an independent predictor of CAD.[34]

Other heart diseases

Valvular heart diseases lead to either volume or pressure overload of the ventricles. Increased serum levels of BNP and NT-proBNP could be useful in evaluating the severity and prognosis of valve diseases. In patients with valvular aortic stenosis, increased levels of BNP and NT-pro BNP were found to be related to disease severity, functional status, and disease progression, with a decline of elevated values after successful valve replacement.[353637] Diagnostic utility in regurgitant valvular lesion, however, are limited. There is evidence that BNP and NT-proBNP assessment might play a role in the diagnostic work up of patients with valvular heart diseases and optimal timing of valve surgery but the clinical benefits that can be derived have not yet been established. Elevated levels of BNP and NT-proBNP in atrial fibrillation in the absence of heart failure have been linked to poor prognosis.[17]

Clinical information that can be obtained from BNP and NT-proBNP assessment of patients with heart diseases is summarized in Table 5.[18] Though the cut-off value for BNP is < 100 pg/ml to rule out heart failure, but in patients of congenital heart disease with single ventricular physiology, it is 45 pg/ml.[38] Further studies are needed to establish the role of natriuretic peptides in cardiovascular illnesses other than heart failure.

Table 5

Clinical information that can be obtained from BNP and NT-proBNP serum levels in cardiovascular illnesses[18]

Sepsis

Sepsis is a life-threatening condition characterized by systemic inflammatory response syndrome with proven or suspected evidence of microbial infection. BNP and NT-proBNP have been the focus of studies evaluating the severity and prognosis of sepsis; elevated levels of these peptides may prove to be a powerful predictor of mortality in septic patients. The main pathophysiology of increased BNP and NT-proBNP in sepsis is either due to cardiac insufficiency or systemic inflammation. Increased surge of inflammatory cytokines and endotoxin also participate in the expression of BNP gene.[3940] Measurements of BNP and NT-proBNP have been applied in predicting the prognosis of patients with severe sepsis or septic shock. BNP levels in plasma represent a reliable marker for identification of patients developing sepsis-induced myocardial depression. Increased level of BNP and NT-proBNP are found to be associated increased mortality [Table 6].[4142434445] Elevated BNP and NT-proBNP on admission, 3rd and 5th day may be used as a prognostic marker to identify patients with an elevated risk for an adverse outcome.

Table 6

Relationship between increased natriuretic peptides and mortality in cases of severe sepsis and shock

Renal failure

Renal failure most often complicates heart failure. Prevalence of heart failure increases when glomerular filtration rate decreases <60 ml/min. A sizeable proportion (35%) of end-stage renal disease patients have clinical evidence of heart failure.[46] A sub-study of PRIDE revealed a reduced sensitivity and specificity of NT-proBNP in the diagnosis of heart failure in patients with renal failure where serum concentration of NT-proBNP are affected more than BNP levels. There is a consensus that BNP and NT-proBNP are on the higher side despite of any systolic or diastolic heart failure and the increasing serum concentration correlate well with the stage of chronic kidney disease.[4748] Elevated levels of BNP and NT-proBNP decrease after hemodialysis.[49] Diagnosis of heart failure using natriuretic peptides is a challenge in cases of impaired renal function; hence for better predictability, modified values of BNP and NT-proBNP have been suggested by some authors [Table 7].[6144950]

Table 7

Cut-off value BNP and NT-proBNP to diagnose HF in presence of CKD

Cirrhosis of liver

Cirrhotic cardiomyopathy is an under-diagnosed entity. Studies have demonstrated that patients with hepatic cirrhosis have increased plasma concentrations of BNP and NT-proBNP. These markers have been correlated with the severity of hepatic cirrhosis, and with heart dysfunction.[51] BNP could therefore have prognostic value with regard to the evolution of cirrhosis and decompensation. Serum NT-proBNP level has been shown to correlate directly with the degree of liver dysfunction (lower albumin, increased international normalized ratio (INR), presence of ascites, higher Child-Turcott-Pugh and Modified End Stage Liver Disease scores). It also represents a useful marker to demonstrate the existence of increased left atrial volume and cardiac diastolic dysfunction.[52] It was observed that patients undergoing liver transplantation fair badly if BNP level is higher than 391 pg/ml. Thus raised BNP level may be an early marker for heart dysfunction related to cirrhosis.[53]

Diabetes

Patients of diabetes with cardiac dysfunction have higher values of BNP and NT-proBNP, which are associated with adverse outcome. The most likely explanation for increase in BNP and NT-proBNP levels in patients with diabetes is the presence of diastolic dysfunction.[54] Elevated NT-proBNP is an important risk factor for death and cardiovascular events in type 2 diabetes mellitus patients. Raised baseline NT-proBNP or increase in its level over a period of time is associated with a poor clinical outcome.[55] Elevated plasma levels of NT-proBNP have been seen in patients of diabetes without overt cardiovascular disease; hence it can also serve as a screening tool for early detection of left ventricular dysfunction.[56] Aggressive treatment with medications in patients of diabetes with raised NT-proBNP but free of cardiac disease may be a safe and effective way of primary prevention of cardiac disease.[57]

Pulmonary embolism

BNP and NT-proBNP are not useful in the diagnosis of this life-threatening condition but elevated levels of BNP and NT-proBNP are helpful in identifying the patients who are at risk of death and serious adverse event. Death in pulmonary embolism cases where BNP and NT-proBNP were elevated was 13.3% in contrast to only 1.2% with normal BNP and NT-proBNP. The sensitivity of this test is high in identifying patients at risk for death, but its specificity is low. The positive predictive value for death is low (14%), but its negative predictive value for death is high (99%).[58]

Stroke

In stroke patients, elevated serum BNP on admission may be helpful in confirming a cardio-embolic etiology of stroke. It may also signal increased risk for poor long-term prognosis including death. BNP testing has a role in risk stratification and identifying those stroke patients who will require intensive rehabilitative intervention. NT-proBNP level of > 1583.5 pg/ml was found to be an independent risk factor for in-hospital death. However, BNP levels played no significant role in prediction of outcomes among subjects with noncardio-embolic stroke.[5960]

CHF versus Chronic obstructive pulmonary disease

BNP and NT-proBNP are important blood tests to discriminate between CHF and acute exacerbations of COPD. Patients with CHF have significantly higher levels of natriuretic peptides as compared to patients with acute exacerbations of COPD. Several studies have demonstrated that BNP and NT-proBNP were useful in differentiating acute exacerbations of COPD from CHF [Table 8].[61626364] Patients of acute exacerbation of COPD without corpulmonale or pulmonary hypertension have lower levels of natriuretic peptides. Patients of COPD with corpulmonale had a higher mean BNP level as compared to those without corpulmonale (73.9 ± 35.8 and 21.0 ± 10.2 pg/ml, respectively).[65] Serum levels of BNP and NT-proBNP are also found to be on higher side in patients of COPD with pulmonary arterial hypertension.

Table 8

BNP and NT-proBNP in patients with CHF and COPD

CONCLUSION

Point-of-care analysis of BNP and NT-proBNP help emergency physicians in managing patients with a variety of conditions. They are primarily helpful in difficult-to-diagnose causes of dyspnea. They are a strong tool in the ED to differentiate CHF from its various mimics and are also helpful in monitoring of heart failure therapy. BNP and NT-proBNP are powerful prognostic tools in CHF and various other clinical settings. Patient's factors like age, sex, obesity, anemia, and renal dysfunction might alter the plasma concentration of BNP and NT-proBNP; so in the presence of these conditions, values of natriuretic peptides should be interpreted cautiously. Evidence suggests that BNP and NT-proBNP may also assist in deciding optimal treatment of various other clinical conditions. Serial measurement of BNP and NT-proBNP can suggest change in prognosis of the patient in response to therapy. Despite extensive utility of BNP and NT-proBNP in the ED in CHF, further studies are needed to consolidate the diagnostic and prognostic significance of these peptides in various other clinical conditions.