Advances in congestive heart failure management in the intensivecare unit: B-type natriuretic peptides in evaluation of acute heartfailure

Torbjørn Omland, MD, PhD, MPH

Acute heart failure can be de-fined as the rapid onset ofsymptoms and signs secondaryto abnormal cardiac systolic or

diastolic function (1). The clinical syn-drome of acute heart failure is character-ized by one or more of the following:reduced cardiac output, tissue hypoperfu-sion, increased pulmonary artery occlu-sion pressure, and tissue congestion.Heart failure can present in patientswithout previously recognized cardiacdysfunction (de novo) or as the acutedecompensation of chronic congestive

heart failure (CHF). Acute heart failure isassociated with intense patient discom-fort and, despite recent advances in ther-apy, still carries a high mortality rate.Because acute CHF requires urgent treat-ment, early evaluation of patients is cru-cial for appropriate selection and moni-toring of therapy. This evaluation can becomplex and relies on integration of thebedside evaluation and information avail-able from invasive or noninvasive diag-nostic techniques (2). This article reviewsthe role that B-type natriuretic peptides(BNPs) play in the evaluation of acuteheart failure, with special emphasis ontheir utility in the intensive care unit(ICU).

Biology of B-Type NatriureticPeptide

BNP was first identified in porcinebrain in 1988 and originally was termedbrain natriuretic peptide (3). Subse-quently, it was detected in ventricularcardiomyocytes, and the ventricular myo-cardium was later recognized as the ma-jor source of circulating BNP (4). BNP iscommonly regarded as an exclusively

ventricular-derived hormone, but theconcentration of BNP appears to behigher in atrial than in ventricular tissue.Taking into account tissue weight,however, the total amount of BNP mes-senger RNA has been suggested to bethree times higher in the ventriclesthan in the atria (5).

BNP shares structural and physiologicfeatures with atrial natriuretic peptide.Despite being encoded by separate genes,the two peptides show a high degree ofprimary structure homology and share acommon ring structure. The second mes-senger cyclic guanosine monophosphatemediates the main physiologic actions ofatrial natriuretic peptide and BNP. Bind-ing to guanylyl cyclase-coupled, high-affinity natriuretic peptide-A receptors ontarget cells increases intracellular levelsof cyclic guanosine monophosphate, re-sulting in vasodilation, natriuresis, diure-sis, and inhibition of renin release andaldosterone production (5, 6).

BNP is synthesized as a longer precur-sor peptide or prohormone (proBNP) andsubsequently split into a biologically ac-tive C-terminal and an inactive N-terminal fragment by the enzyme corin

From the Department of Medicine, Akershus Uni-versity Hospital, Lørenskog, Norway.

During the past 5 years Dr. Omland has receivedresearch support from Roche Diagnostics and AbbottLaboratories; speaker’s honoraria from Abbott Labora-tories, Bayer Diagnostics, and Roche Diagnostics; andconsultancy honoraria from Roche Diagnostics, man-ufacturers of BNP and NT-proBNP assays.

Address requests for reprints to: Torbjørn Omland,MD, PhD, MPH, Department of Medicine, AkershusUniversity Hospital, NO-1478 Lørenskog, Norway.E-mail: torbjorn.omland@medisin.uio.no

Copyright © 2007 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000296266.74913.85

Background: Circulating concentrations of B-type natriureticpeptide (BNP) and the aminoterminal fragment (NT-proBNP) of itsprohormone (proBNP) are increased in congestive heart failure inproportion to the severity of symptoms, the degree of left ven-tricular dysfunction, and cardiac filling pressures. Following theintroduction of rapid, automated assays for determination of BNPand NT-proBNP, these peptides are increasingly used for diag-nostic and prognostic purposes.

Objective: To review studies evaluating the diagnostic andprognostic value of BNP and NT-proBNP, with special emphasison their performance as indicators of acute heart failure in theintensive care unit.

Results: In patients presenting with acute dyspnea, both BNPand NT-proBNP are accurate indicators of acute heart failure andprovide prognostic information above and beyond conventional

risk markers. Increased plasma levels of BNP and NT-proBNP arenot specific for heart failure and may be influenced by a variety ofcardiac and noncardiac conditions commonly seen in the inten-sive care unit, including myocardial ischemia, cardiac arrhyth-mias, sepsis, shock, anemia, renal failure, hypoxia, acute pulmo-nary embolism, pulmonary hypertension, and acute respiratorydistress syndrome.

Conclusions: The diagnostic performance of BNP and NT-proBNP as indicators of acute heart failure depends on the clinicalsetting. In the intensive care unit, particular caution should beused in the interpretation of elevated BNP and NT-proBNP levels.(Crit Care Med 2008; 36[Suppl.]:S17–S27)

KEY WORDS: B-type natriuretic peptide; heart failure; dyspnea;shock; sepsis

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(5). The processing of proBNP to N-terminal fragment (NT-proBNP) and the32-amino acid, biologically active BNPprobably occurs both intra- and extracel-lularly. In human cardiac tissue, BNP ap-pears to be found predominantly in the32-amino acid form, but a significantamount is also stored as the intact 108-amino acid precursor peptide, proBNP.ProBNP is only partially stored in gran-ules, and the regulation of BNP synthe-sis and secretion apparently takes placeat the level of gene expression. Both thebiologically active 32-amino acid C-terminal fragment (BNP), the 76-aminoacid N-terminal fragment (NT-proBNP),and other high-molecular fragments,possibly intact proBNP 1–108, arefound circulating in human plasma (7).Interestingly, a recent study usingquantitative mass spectral methodologyreported the absence of circulating 32-amino acid BNP in advanced heart fail-ure, suggesting the existence of alteredforms of BNP that contribute to thehigh levels measured by conventionalassays (8). A schematic and simplifieddrawing showing the cleavage ofproBNP into BNP and NT-proBNP isdepicted in Figure 1.

Stretching of the atrial and failingventricular myocardium is a potent stim-ulus for BNP production, which probablyoutweighs the influence of other modu-lating factors of natriuretic peptide pro-duction in most patients with heart fail-ure (9). BNP expression and release fromcardiomyocytes can be stimulated by avariety of endocrine, paracrine, and auto-crine factors activated in CHF as well asfactors like norepinephrine, angiotensinII, endothelin-I, glucocorticoids, andproinflammatory cytokines.

Although the N- and C-terminal frag-ments of proBNP probably are secreted ina 1:1 fashion, circulating levels may differbecause of different clearance character-istics. The in vivo plasma half-life of BNPhas been estimated to be approximately21 mins (4, 10). Investigations in sheepsuggest that the circulating half-life ofNT-proBNP is approximately 70 mins(11), but studies in humans have yet to beperformed. Clearance of BNP occurs bothvia binding to clearance receptors and bythe actions of enzyme neutral endopepti-dase. The mechanisms involved in clear-ance of NT-proBNP are less well charac-terized. Renal impairment, a commoncomorbidity in patients with CHF as wellas in many other ICU patients, reducesclearance of both BNP and NT-proBNP

(12). Characteristics of BNP and NT-proBNP are summarized in Table 1.

Assays for BNP and NT-proBNP

During the past few years, several fullyautomated, rapid assays for determina-tion of BNP and the N-terminal fragmentof its prohormone (NT-proBNP) have be-come commercially available, permittingtheir use in the clinical setting. Theseinclude both high-throughput automatedplatforms and point-of-care tests. Both

preanalytic and analytic issues are impor-tant for the proper interpretation of testresults, and clinicians should be aware ofthe following practical points: Plastictubes containing EDTA are desirable forBNP determination, whereas NT-proBNPcan be measured in serum or plasma andcollected in glass or plastic tubes. ForBNP, refrigeration may be required if theinterval between blood collection andanalysis is �4 hrs. On the other hand, nosignificant loss of NT-proBNP immuno-reactivity is apparent after 48 hrs at room

—COOH

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BNP Receptors onbrain, vasculature,adrenals, kidney(NPR A,B,C)

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123

Figure 1. Schematic drawing showing cleavage of prohormone of B-type natriuretic peptide (proBNP)into the biologically active C-terminal fragment, B-type natriuretic peptide (BNP), and the inactiveN-terminal fragment, NT-proBNP. NPR, natriuretic peptide receptor.

Table 1. Characteristics of B-type natriuretic peptide (BNP) and N-terminal fragment of prohormoneof BNP (NT-proBNP)

Characteristic BNP NT-proBNP

Prohormone fragment C-terminal (proBNP 77–108) N-terminal (proBNP 1–76)Molecular weight, kDa 3.5 8.5Physiological activity Active Probably inactiveFDA-approved cutoff values

for heart failurediagnosis, pg/mL

100 Age �75 yrs: 125Age �75 yrs: 450

Clearance mechanisms Clearance receptorsNeutral endopeptidase

Unclear, renal clearancemay contribute

Plasma half-life, mins 21 60–120In vitro stability 24 hrs at room temperature �3 days at room

temperatureAnalyzed in Whole blood and EDTA

plasma (plastic tubes)Serum and plasma

FDA, Food and Drug Administration.

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temperature. Although existing BNP as-says correlate closely, BNP assays are notcurrently analytically equivalent due tolack of assay standardization.

BNP in Cardiovascular Disease

Soon after the discovery of BNP pro-duction in the human myocardium, itbecame clear that tissue and circulatingconcentrations of BNP are elevated inCHF in proportion to the severity ofsymptoms (13), the degree of left ventric-ular dysfunction (14), and cardiac fillingpressures (4, 15). Both systolic and dia-stolic impairment of the left ventricle canresult in elevated circulating natriureticpeptide levels (16, 17), even in mildlysymptomatic or asymptomatic patientswith left ventricular impairment (15, 18).

In addition to systolic and diastolic leftventricular dysfunction, BNP and NT-proBNP levels are elevated in a broadspectrum of cardiovascular diseases, in-cluding acute coronary syndromes, stablecoronary heart disease, valvular heart dis-ease, acute and chronic right ventricularfailure, and left and right ventricular hy-pertrophy secondary to arterial or pulmo-nary hypertension (6). Activation of neu-rohormonal systems with vasoconstrictor,antidiuretic, proinflammatory, hypertro-phic, and cytoproliferative actions is be-lieved to play a pathophysiological role inthe progression of many of these conditions(19). The natriuretic peptides possessbeneficial and compensatory propertiesthat counteract these vasoconstrictorneurohormonal systems. Table 2 summa-rizes some factors associated with higherplasma levels of BNP and NT-proBNP.

Diagnosis of CHF in the AcutelyDyspneic Patient

The clinical diagnosis of CHF can bechallenging, particularly in patients pre-senting with acute shortness of breath inthe urgent care setting. Information ob-

tained from clinical history and physicalexamination as well as from electrocar-diogram and chest radiograph may pro-vide valuable clues as to whether CHF isthe cause of symptoms, but additionaldiagnostic tests, including echocardiog-raphy, may be required to obtain a moredefinite diagnosis (20). However, a help-ful history may not be obtainable in theacutely ill patient with dyspnea. Physicalsigns, including pulmonary rales, edema,a third heart sound, and elevated jugularvenous pressure, may be absent, particu-larly if the patient already receives phar-macologic therapy. Findings on the chestradiograph, including redistribution andinterstitial or alveolar edema, are rela-tively specific but insensitive signs ofCHF (21). A normal electrocardiogram isseen infrequently in patients with CHF,but electrocardiographic abnormalitieshave a low positive predictive value forCHF (22). Many patients with acuteshortness of breath may have difficultiesin lying still, and obesity and chronicobstructive pulmonary disease, factorscommonly seen in acutely dyspneic pa-tients, may result in inferior echocardio-graphic image quality. A misdiagnosismay have serious consequences, particu-larly if inappropriate therapy is initiated.For instance, sympathomimetic aminesand �-adrenergic agonists may provokearrhythmias and angina in patients withdyspnea secondary to CHF.

BNP in Patients With AcuteDyspnea

Today, the best documented and mostwidely used clinical application of BNPtesting is for the emergency diagnosis ofCHF in patients presenting with acutedyspnea. Although the results of a small-scale study published in 1994 suggestedthat BNP measurements could be usefulin this setting (23), it was not until thedevelopment of rapid analytic tests and

the publication of the Breathing NotProperly multinational study in 2002 thatBNP measurements were introduced intoclinical practice. In this landmark multi-center diagnostic test evaluation trial,which included 1,586 patients who vis-ited the emergency department with amain complaint of acute dyspnea, a rapidpoint-of-care fluorescence immunoassaywas used for BNP determination (24). Di-agnosis of heart failure was adjudicatedby cardiologists blinded to the BNP re-sults. In this study, BNP concentrationwas found to provide strong and incre-mental diagnostic information to conven-tional historical, clinical, or other labora-tory tests and to have greater diagnosticaccuracy for the diagnosis of heart failurethan the emergency department physi-cian, using all other available informa-tion. Using a cutoff of 100 pg/mL, theoverall diagnostic accuracy was 83.4%and the area under the receiver operatingcharacteristic curve for BNP was 0.91(95% confidence interval 0.90 – 0.93)(Fig. 2). Although BNP testing performedslightly better in men than in women andin younger (�70 yrs) than older patients,the overall accuracy was very good re-gardless of these demographic factors.Importantly, BNP performed well in pa-tients with an intermediate (20% to 80%)pretest probability of heart failure, asevaluated by the emergency departmentphysician (25). In these subjects, whoconstituted 43% of the total study cohort,the BNP �100 pg/mL cutoff classified74% correctly.

Very similar results were later re-ported for NT-proBNP, using a clinicalchemistry laboratory-based analytic plat-form, in the N-terminal Pro-BNP Investi-gation of Dyspnea in the Emergency de-partment (PRIDE) study (26). Thisprospective, single-center study included599 patients with acute dyspnea present-ing to the emergency department of Mas-sachusetts General Hospital in Boston,the primary objective being to comparethe diagnostic accuracy of NT-proBNPwith that of clinical assessment for iden-tifying acute heart failure. In this study,the area under the receiver operatingcharacteristic curve for NT-proBNP was0.94, which compared favorably with0.90 for clinical assessment (p � .009).Several decision thresholds were evalu-ated and the single best cutoff wasfound to be 900 pg/mL, a cutoff thathad an overall diagnostic accuracy of87% (sensitivity 90%, specificity 85%).Using the lower cutoff of 450 pg/mL

Table 2. Major causes of elevated plasma levels of B-type natriuretic peptide (BNP) and N-terminalfragment of prohormone of BNP (NT-proBNP)

Elevated stretch of the myocardium due to impaired systolic and/or diastolic function (e.g., acuteand chronic congestive heart failure, acute and chronic cor pulmonale)

Ventricular hypertrophy (e.g., hypertensive heart disease)Volume expansion and consequent elevated pressure/distension (e.g., renal or hepatic failure)Decreased renal clearance (e.g., acute and chronic renal failure, advanced age)Neurohormonal and cytokine stimulation (e.g., sepsis, shock)Myocardial ischemia (e.g., unstable angina, acute myocardial infarction)Hypoxia (e.g., acute pulmonary embolism, cyanotic congenital heart disease)Tachycardia (e.g., atrial fibrillation, ventricular tachycardia)Female gender

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increased sensitivity to 98% at the costof a decreased specificity of 76% and anoverall diagnostic accuracy of 83%. Ta-ble 3 summarizes optimal confirmatoryand exclusionary decision limits foracute heart failure based on a pooledanalysis of studies evaluating the diag-nostic value of NT-proBNP in acutelydyspneic patients (27).

Another important study suggestingthat BNP determination on presentationto the emergency department can trans-late into improved management and re-

duced cost was the B-type NatriureticPeptide for Acute Shortness of BreathEvaluation (BASEL) study (28). This pro-spective, randomized trial evaluated theeffect of rapid point-of-care BNP testingon time to discharge and total cost oftreatment in 452 acutely dyspneic pa-tients. A diagnostic strategy including asingle rapid measurement of BNP in theemergency department was associatedwith reduced need for intensive care andshorter time to discharge, which togethertranslated into reduced total cost of treat-

ment, compared with those diagnosed ina standard manner without BNP assess-ment. These results were recently corrob-orated by the Canadian IMPROVE-CHFstudy, which included 501 patients pre-senting with shortness of breath to sevenemergency departments across Canada(29). One major objective of this random-ized, controlled study was to evaluatewhether the measurement of NT-proBNPimproves the overall management of pa-tients presenting with suspected acuteheart failure and whether the knowledgeof NT-proBNP levels on presentation re-sulted in reduced resource utilization andhospital cost. Although it was reportedthat NT-proBNP measurements were as-sociated with an average cost saving ofnearly $1,000, duration of ICU or totalhospital stay did not differ between theusual care and NT-proBNP group. More-over, in the report it was not clearwhether the savings were related to bet-ter and more rapid treatment or to lessuse of diagnostic testing.

The clinical utility of BNP testingclearly depends on the clinical setting.BNP may be far less discriminative in thediagnosis of systolic dysfunction in well-treated patients with chronic CHF andmild symptoms than in acutely decom-pensated patients with severe shortnessof breath (30). Moreover, the results ob-tained in studies of acutely dyspneic pa-tients cannot be extrapolated to heartfailure patients who present with pre-dominantly low-output symptoms (e.g.,fatigue or anorexia).

Can BNP Be Used as aSurrogate for SpecificHemodynamic Measurements?

After the realization that BNP levelsare increased in heart failure, a logicalnext step was to evaluate whether BNPcan be used as a surrogate marker ofFigure 2. Main results of the Breathing Not Properly Multinational study. See text for details.

Reprinted with permission from Maisel et al (24). BNP, B-type natriuretic peptide.

Table 3. Recommended decision thresholds for N-terminal fragment of prohormone of B-type natriuretic peptide (NT-proBNP) in the diagnosis of acuteheart failure

Age, yrs Optimal Cutoff, pg/mL Sensitivity, % Specificity, % PPV, % NPV, % Accuracy, %

Confirmatory (rule in) decision limits�50 450 97 93 76 99 9550–75 900 90 82 82 88 85�75 1800 85 73 92 55 83Overall 90 84 86 66 86

Exclusionary (rule out) decision limitAll ages 300 99 62 55 99 83

PPV, positive predictive value; NPV, negative predictive value.Adapted from Januzzi et al (27).

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hemodynamic measurements and ven-tricular function, including ventricularfilling pressures and ejection fraction.Early small-scale studies suggested thatBNP levels could be used to identify pa-tients with acute myocardial infarctionand ejection fraction �40% (31). Subse-quent studies, including substantiallylarger patient populations, in most casesfailed to confirm a close correlation be-tween BNP levels and ejection fraction(15, 27, 32, 33). Although a significantcorrelation exists between BNP and sys-tolic function, this correlation is not suf-ficiently strong to make BNP or NT-

proBNP reliable surrogate indicators ofejection fraction (Fig. 3). Similarly, al-though ventricular stretch clearly repre-sents a major stimulus for BNP release,the correlations between BNP and pul-monary artery occlusion pressure (PAOP)or left ventricular end-diastolic pressuresare only moderately strong, not permit-ting reliable information to be obtainedconcerning filling pressures based on aBNP or NT-proBNP test in individual pa-tients (15, 34). The lack of a close corre-lation between BNP and filling pressuresmay seem surprising, given that ventric-ular stretch is the predominant stimulus

for BNP release in experimental models.In patients, however, a number of cardiacand noncardiac factors are co-determi-nants of circulating BNP concentrations,and the variability in BNP and NT-proBNP that can be ascribed to left ven-tricular filling pressures is relativelymodest.

Many factors that cause significant in-terindividual differences in BNP and NT-proBNP concentrations in patients withsimilar hemodynamic status usually re-main relatively unaltered in a single pa-tient (e.g., age, gender, and renal func-tion). Accordingly, serial BNP and NT-proBNP measurements may be usefultools for monitoring hemodynamicchanges in individual patients. In groupsof patients, average BNP and NT-proBNPlevels clearly drop in parallel with reduc-tions in left ventricular preload (34,35)(Fig. 4). Still, it has proved difficult toaccurately predict the change in a hemo-dynamic variable, such as PAOP, based onthe change in BNP levels. In other words,a given reduction in BNP and in PAOP inone patient may differ substantially fromthe reduction in BNP level induced by asimilar drop in PAOP in another patient.Thus, a significant reduction in BNP dur-ing therapy strongly suggests a reductionin PAOP, but the magnitude of the de-crease cannot be reliably predicted by thechange in BNP in the individual patient.This may be of particular importance inthe monitoring of patients in the ICUwith sepsis or shock, in whom endoge-nous or exogenously administered sub-Figure 3. Association between N-terminal fragment B-type natriuretic peptide (NT-proBNP) and left

ventricular ejection fraction. Reprinted with permission from Januzzi et al (27).

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Figure 4. Effect of reduction in cardiac filling pressures on plasma natriuretic peptide levels. RAP, right atrial pressure; PCWP, pulmonary artery occlusionpressure; ANP, A-type natriuretic peptide; BNP, B-type natriuretic peptide; NT-proANP, N-terminal fragment of prohormone of ANP. Adapted from Johnsonet al (35).

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stances may affect BNP concentrationsindependently of hemodynamic status.

Can BNP Be Used toDiscriminate Between Systolicand Diastolic Heart Failure?

Symptomatic heart failure may becaused by both systolic and diastolic dys-function, and variable degrees of bothsystolic and diastolic dysfunction arecommonly observed in the same individ-ual (36). Circulating levels of BNP andNT-proBNP can be elevated secondary toboth systolic and diastolic dysfunction ofthe left ventricle, and particularly highlevels may be observed in those withcombined systolic dysfunction and a re-strictive filling pattern (37). As heart fail-ure with preserved systolic ventricularfunction is prevalent, particularly in theelderly, BNP and NT-proBNP have provedto be less reliable indicators of systolicdysfunction than of clinical heart failure(38). Moreover, BNP and NT-proBNP can-not reliably discriminate between systolicor diastolic dysfunction as the cause ofheart failure (17).

What Causes BNP Elevation inPatients Without CHF?

A number of factors other than ven-tricular function, including advanced pa-tient age and female gender, decreasedbody mass index, decreased renal func-tion, left ventricular hypertrophy, historyof myocardial infarction and ongoing car-diac ischemia, pulmonary embolism,chronic right ventricular failure, and car-diac arrhythmias, have been shown toinfluence circulating BNP and NT-proBNP levels. Clearly, the presence ofany of these factors may confound therelationship between elevated BNP andNT-proBNP levels and the diagnosis ofacute heart failure and thus impair thediagnostic accuracy of BNP and NT-proBNP testing (12, 39–42). Most stud-ies, however, have assessed only the sig-nificance of single factors, and untilrecently their relative and independentimportance as confounders had not beenevaluated. In a recent analysis based onthe Breathing Not Properly multinationalstudy, multivariable modeling was usedto identify factors independently associ-ated with elevated BNP levels in the ab-sence of heart failure (43). Five indepen-dent predictors of elevated BNP levelsin the absence of acute heart failurewere identified: low hemoglobin values,

low body mass index, a medical historyof atrial fibrillation, radiographic car-diomegaly, and advanced age of the pa-tient. Notably, renal function did notemerge as an independent predictor ofBNP, possibly because of colinearitywith patient age.

In a pooled analysis of four studiesthat included 1,256 patients with acutedyspnea, 215 patients had an intermedi-ate NT-proBNP concentration, of whom116 subjects (54%) were classified as hav-ing a diagnosis of acute heart failure (44).Multivariable modeling was used to iden-tify predictors of acute heart failure inpatients with NT-proBNP levels in thegray zone (defined as 300–450 pg/mL inpatients aged �50 yrs, 300–900 pg/mL inpatients aged 50–75 yrs, and 300–1800pg/mL in those �75 yrs of age). The ab-sence of cough, use of loop diuretics onpresentation, paroxysmal nocturnal dys-pnea, and jugular vein distension wereindependently associated with a diagnosisof acute heart failure. Importantly, anintermediate (or gray zone) NT-proBNPconcentration was associated with in-creased mortality compared with thosewith NT-proBNP �300 pg/mL regardlessof a diagnosis of acute heart failure ornot. Accordingly, a gray-zone BNP or NT-proBNP should not be misinterpreted as afalse-positive or false-negative result butrather as a result that signifies an inter-mediate risk of death.

What Causes “Normal” BNPLevels in Patients With CHF?

In patients with documented CHF,BNP and NT-proBNP levels may occa-sionally be below the decision thresholdfor heart failure. In stable ambulatorypatients with symptomatic systolic CHF,approximately 20% of patients were re-ported to have BNP levels �100 pg/mL(30). These patients with so-called nor-mal BNP values were more likely to beyounger, to be female, to have nonisch-emic pathogenesis, and to have betterpreserved renal and ventricular functionand less likely to have atrial fibrillation.In acutely dyspneic patients, false-negative BNP and NT-proBNP results areless common but may be seen in patientswith flash pulmonary edema and thosewith severe obesity (40). Etiology of heartfailure at the level of the atrium (e.g.,mitral stenosis or acute mitral regurgita-tion) is another possible cause of unex-pectedly low BNP and NT-proBNP levels.

Prognostic Value in Acute CHF

Given the association between bothBNP and NT-proBNP and the severity ofheart failure, it is not surprising that thatthese peptides are strongly predictive ofthe incidence of mortality and heart fail-ure hospitalizations. However, multiplestudies have shown that BNP and NT-proBNP provide prognostic informationabove and beyond conventional riskmarkers, including clinical assessmentand indices of ventricular function. Thishas been documented in large popula-tions of patients with stable CHF (45) aswell as in patients with acute decompen-sation (46, 47) and in patients presentingwith acute dyspnea (48, 49). The RapidEmergency Department Heart FailureOutpatient Trial (REDHOT) evaluated theassociation between BNP levels, per-ceived heart failure severity by the emer-gency department physician, clinical de-cision making, and outcomes in 464acutely dyspneic patients with elevatedBNP (i.e., �100 pg/mL), of whom 90%were admitted (50). Interestingly, BNPlevels did not differ between patients ad-mitted and those discharged, and no cor-relation was observed between BNP levelsand perceived disease severity. By logisticregression analysis, the intention of theemergency department physician to ad-mit or discharge was not related to 90-day outcome. Conversely, a single BNPmeasurement in the emergency depart-ment was predictive of the combined endpoint of mortality and heart failure ad-missions.

Some studies have suggested that inpatients with acute heart failure, BNPlevels at discharge are more closely asso-ciated with prognosis than concentra-tions on admission. In one study of 72patients admitted with decompensatedheart failure, those with high levels onpresentation and at discharge were mostlikely to experience death or readmissionwithin 30 days (47). The value of serialtesting of NT-proBNP was confirmed in astudy of 182 consecutive patients hospi-talized with decompensated heart failurewho were followed for 6 months. Al-though several variables were related tooutcome, in a multivariate model dis-charge NT-proBNP emerged as the stron-gest prognostic indicator (46). These ob-servations suggest that although BNP orNT-proBNP measurements on presenta-tion are helpful for diagnostic purposes, arepeated test on discharge may provideadditional prognostic information of con-

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sequence for the intensity of therapy andthe interval between outpatient controlvisits following discharge. Minor changesin BNP and NT-proBNP should, however,be interpreted cautiously as the intrain-dividual variability of BNP and NT-proBNP levels may be as high as 40% (51,52).

Practical Recommendations forBNP Testing

Adapting a strategy originally pro-posed by Stevenson (53), Maisel (54) pro-posed a conceptual model concerning cir-culating concentrations of BNP and NT-proBNP in patients with decompensatedCHF (Table 4). According to this model,plasma BNP comprises two components:a basal or “dry” BNP level observed in theeuvolemic state and the additional BNPproduction caused by volume overload.The sum of basal and the volume over-load-induced concentrations will deter-mine the “wet” BNP levels observed dur-ing acute decompensation. The dry BNPlevel is the more important determinantof repeated episodes of decompensationand readmission. Moreover, knowledge ofthe dry BNP concentration is likely to beuseful for monitoring clinically stable pa-tients. An increase from the baseline dryBNP level may indicate the need for in-tensified diuretic or other vasodilatortherapy. Failure of BNP to fall duringtreatment may have different explana-tions. Some patients may have very ad-vanced heart failure with high BNP levelsin the dry state, a condition associatedwith a poor prognosis. Other patientsmay have increasing plasma concentra-tions of BNP and NT-proBNP because ofincreasing renal dysfunction.

Cardiac Dysfunction in the ICU

By definition, most patients in the ICUare critically ill and at high risk for com-plications and death. Cardiac dysfunc-tion, transient or permanent, is relativelycommon in certain groups of patients in

the ICU. The prevalence of cardiac dys-function, however, depends critically onthe characteristics of the study popula-tion and the criteria and methods used todiagnose cardiac abnormalities. In a gen-eral intensive care unit sample of 121consecutive patients included during a9-wk period, approximately 30% wereidentified as having a cardiac abnormal-ity, as evaluated by history, electrocardio-gram, chest radiograph, and echocardiog-raphy (55). In patients with severe sepsisand septic shock, about half of the pa-tients were reported to have some degreeof myocardial dysfunction (56). Echocar-diographic findings of right or left ven-tricular dysfunction may have importantconsequences for evaluation and manage-ment of critically ill patients. However,transthoracic echocardiography in thispopulation may be technically challeng-ing, and image quality is frequently sub-optimal. Moreover, experienced echocar-diographers may not be available on a24-hr basis. In patients with shock, addi-tional hemodynamic information may berequired, particularly concerning cardiacfilling pressures and peripheral and pul-monary vascular resistance. Invasive he-modynamic monitoring with pulmonaryartery catheters is one approach to pa-tients with shock in the ICU, but theclinical efficacy of such monitoring is un-proven (57, 58). Information concerningcardiac performance and hemodynamicstatus is, however, often desirable in thecritically ill, and recently circulating bi-omarkers, including BNP and NT-proBNP,have been proposed as useful diagnosticand prognostic tools in this setting.

BNP Measurements in the ICU

Given that preexisting cardiovasculardisease, critical illness-associated tran-sient myocardial impairment, and renalimpairment, alone or in combination, arecommon phenomena in ICU patients, it isnot surprising that many patients havesome degree of BNP and NT-proBNP el-

evation. In one analysis, the presence ofpreexisting cardiac disease was the singlemost important determinant of BNP ele-vation in a general ICU, accounting fornearly 50% of BNP variability (55). How-ever, numerous other factors may causeBNP and NT-proBNP elevation in criticallyill patients. Because ICU patients comprisea heterogeneous group and because mech-anisms responsible for increased BNP pro-duction or decreased clearance may differaccording to the index diagnosis of the pa-tient, broad diagnostic categories are dis-cussed briefly next.

Sepsis and Shock. Several studies haveexamined whether BNP and NT-proBNPcan be used to replace invasive hemody-namic monitoring for guidance of fluidresuscitation and vasopressor therapy inpatients with sepsis or septic shock (59).One study that included 17 patients withseptic shock showed higher levels in pa-tients with septic shock than in age-matched control subjects, but absoluteconcentrations were very low and did notcorrelate with filling pressures (60). Inanother study of 40 patients in the ICUrequiring hemodynamic monitoring, ofwhom 12 had a diagnosis of sepsis oracute respiratory distress syndrome, bothBNP and NT-proBNP were markedly ele-vated but only weakly correlated withPAOP (61). Renal function was an impor-tant determinant of both BNP and NT-proBNP. Moreover, renal impairmentmodulated the association between natri-uretic peptides and PAOP. In anotherstudy of 49 patients with shock, of whom42 were classified as noncardiogenic, nocorrelation with PAOP was observed, buta low BNP level effectively ruled out adiagnosis of cardiogenic shock (62). In arecent study, 249 consecutive patientswere screened for the presence of severesepsis or septic shock and for acute heartfailure (63). Patients with sepsis (n � 24)and heart failure (n � 51) did not havesignificantly different BNP or NT-proBNPlevels, despite markedly different hemo-dynamic patterns (sepsis vs. heart failure:mean pulmonary artery pressure 16 �4.2 vs. 22 � 5.3 mm Hg, and cardiacindex 4.6 � 2.8 vs. 2.2 � 0.6 L/min/m2).In summary, although some studies re-port significant correlations betweenBNP and PAOP, the association is gener-ally weak. This is probably due to themajor contribution of other stimuli fornatriuretic peptide production and re-duced clearance in ICU patients. Conse-quently, BNP and NT-proBNP determina-tion should not be employed as a

Table 4. Strategy for triage and therapy of patients with acute heart failure using B-type natriureticpeptide (BNP) and clinical evaluation

No Congestion at Rest Congestion at Rest

Adequate perfusion at rest Warm and dryBNP 100–400

Warm and wetBNP �600

Low perfusion at rest Cool and dryBNP 400–1000

Cool and wetBNP �1000

Adapted from Stevenson (53) and Stevenson and Maisel (54).

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substitute for invasive hemodynamicmonitoring in the ICU.

Realizing the limitations of BNP andNT-proBNP measurements as a surrogatefor pulmonary artery catheterization, apossible alternative approach proposed byJanuzzi et al. (64) could be to use thesepeptides to identify patients who may notrequire insertion of a pulmonary arterycatheter. The rationale for this approachis based on the high negative predictivevalue of BNP and NT-proBNP (64). In thestudy by Januzzi et al., NT-proBNP�1200 pg/mL had a negative predictivevalue of 92% for the combination of acardiac index �2.2 L/min/m2 and PAOP�18 mm Hg.

Limited and conflicting data exist con-cerning the effect of fluid loading andcatecholamine therapy on BNP and NT-proBNP levels. In one study, fluid loadingwas found not to be an independent pre-dictor of NT-proBNP levels (65). Anotherstudy reported that patients with left ven-tricular fractional area contraction �0.5,as assessed by transesophageal echocar-diography, had higher BNP levels and hadreceived more intravenous fluids thanthose with left ventricular fractional areacontraction �0.5.

Despite important limitations as a di-agnostic tool for acute heart failure inICU patients, both BNP and NT-proBNPmay provide useful prognostic informa-tion. In one study of patients with severesepsis or septic shock, high BNP levelscorrelated with ventricular dysfunctionand mortality (56). Similarly, in a cohortof 49 patients with mainly noncardio-genic shock, high levels of both BNP andNT-proBNP were associated with in-creased mortality (62, 64) (Fig. 5). Impor-tantly, BNP and NT-proBNP predicted

mortality independently of conventionalrisk markers, including Acute Physiologyand Chronic Health Evaluation II scores.However, not all studies report an asso-ciation with prognosis. In a study of 78patients admitted to a general ICU, patientswith sepsis (n � 35) had higher BNP levelsthan patients without sepsis, but BNP didnot predict in-hospital survival (66).

BNP in Pulmonary Disease. The use-fulness of BNP and NT-proBNP as indica-tors of heart failure in acutely dyspneicpatients depends critically on the premisethat patients with dyspnea due to pulmo-nary causes, of whom chronic obstructivepulmonary disease is the most common,have low circulating concentrations ofthese peptides. A considerable proportionof patients with respiratory failure may,however, have levels that exceed the con-ventional cutoff for heart failure (67). Theinterpretation of this observation is com-plicated by the fact that coronary arterydisease and chronic obstructive pulmo-nary share risk factors and often coexistin the same individual. Underdiagnosis ofheart failure in chronic obstructive pul-monary disease may not be uncommon.Unfortunately, in patients with respira-tory failure, neither BNP nor NT-proBNPappears to differentiate between a low vs.high PAOP state (68). One reason for thismay be that a significant proportion of pa-tients with chronic obstructive pulmonarydisease and respiratory failure will have ev-idence of right heart failure, a stimulus forBNP production.

The majority of patients with acuterespiratory distress syndrome withoutconcomitant shock or acute cor pulmo-nale have BNP and NT-proBNP levels be-low the threshold used for heart failurediagnosis. However, a considerable pro-

portion of patients will develop thesecomplications (69) and may have moder-ately elevated peptide levels (70), al-though usually not in the acute decom-pensated heart failure range. Accordingly,BNP and NT-proBNP may still have someutility to identify left-sided heart failurein these patients, but conventional deci-sion limits are probably suboptimal.

Very recently, the usefulness of NT-proBNP as a tool to identify acute heartfailure during weaning failure in difficult-to-wean patients with chronic obstructivepulmonary disease was assessed (71).Plasma levels of NT-proBNP increasedsignificantly at the end of the spontane-ous breathing trial only in patients withacute cardiac dysfunction. Moreover, NT-proBNP levels at the end of the weaningtrial appeared to perform well in detect-ing acute cardiac dysfunction, althoughstudy power was limited and receiver op-erating characteristic area confidence in-tervals were wide.

BNP in Pulmonary Vascular Disease.Pulmonary hypertension is associatedwith increased right ventricular wallstretch and increased production of BNPand NT-proBNP from the right heart. Inaddition, hypoxia is associated with in-creased expression of the BNP gene. Ac-cordingly, circulating concentrations ofBNP and NT-proBNP are increased in pri-mary pulmonary hypertension (72), per-sistent pulmonary hypertension of thenewborn (73), acute cor pulmonale fol-lowing pulmonary embolism (74) oracute respiratory distress syndrome (70),and right ventricular failure secondary tocongenital heart disease (75). The plasmaBNP and NT-proBNP concentrations ob-served in these conditions are usuallyonly moderately elevated and typicallynot in the range observed in acute leftventricular failure. In general, concentra-tions are increased in proportion to dis-ease severity and are predictive of out-come (72). BNP and NT-proBNP levelsdecrease following successful therapy, forexample, after thromboendarterectomyfor pulmonary hypertension secondary tochronic pulmonary embolism (76). Thesefindings indicate that BNP and NT-proBNP may provide information of po-tential clinical utility concerning the ef-fect of intervention. The diagnostic andprognostic utility of BNP and NT-proBNPin patients with acute pulmonary embo-lism has also been examined (77, 78). Inpatients without right ventricular dys-function, levels are generally low andcannot be used as a diagnostic tool (79).

Figure 5. Mortality by N-terminal fragment of prohormone of B-type natriuretic peptide (NT-proBNP)quartile in intensive care unit patients with shock. Reprinted with permission from Januzzi et al (64).

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However, BNP and NT-proBNP increasein proportion to hemodynamic compro-mise, and elevation of BNP and NT-proBNP has been proposed as a criterionfor thrombolytic therapy because of itsstrong prognostic merit (79). Other in-vestigators, however, argue that the pos-itive predictive value is too low to beclinically useful for this purpose (80).

Other Critical Illnesses. Plasma con-centrations of BNP and NT-proBNP alsoincrease in other critical illness. As men-tioned previously, both BNP and NT-proBNP are elevated in chronic renal fail-ure, but the diagnostic accuracy for heartfailure is not markedly reduced if renal-function-adjusted decision limits areused (12, 81, 82). Sparse data are avail-able concerning the effect of acute renalfailure on natriuretic peptide levels inICU patients, although available evidencesuggests that an inverse relation exists(61, 68). As changes in renal function canoccur rapidly in the ICU, these observa-tions are important. Natriuretic peptidesare also elevated in patients with isch-emic stroke (83) and those with sub-arachnoid hemorrhage (84, 85). Eleva-tion of BNP and NT-proBNP in theseconditions has been attributed to highsympathetic outflow or damage of brainareas with regulatory functions for BNPproduction and may not have prognosticimplications. However, plasma levels insubarachnoid hemorrhage also correlatewith cardiac dysfunction (85).

CONCLUSIONS

BNP and NT-proBNP provide valuableand well-documented biochemical guid-ance for the diagnosis of acute heart fail-ure in patients presenting with acute dys-pnea. These peptides also providepowerful prognostic information in pa-tients with acute heart failure. Circulat-ing levels of BNP and NT-proBNP are,however, influenced by numerous cardiacand noncardiac factors, including myo-cardial ischemia, hypoxia, patient age,gender, and renal function. Conse-quently, BNP and NT-proBNP are sensi-tive but unspecific markers of cardiacstructural and functional abnormalitiesbut can generally not be used as a surro-gate for a single hemodynamic index(e.g., PAOP or ejection fraction). In theICU, many patients may have moderatelyelevated natriuretic peptide levels with-out the presence of left ventricular fail-ure. Conditions other than left ventricu-lar failure commonly associated with

increased BNP and NT-proBNP levels inthe ICU include shock, hypoxia, renal fail-ure, and pulmonary hypertension. As thediagnostic accuracy of BNP and NT-proBNP for left ventricular failure is re-duced in the ICU, BNP and NT-proBNPmeasurements in the ICU should be in-terpreted cautiously and in most casesmay augment but cannot replace infor-mation obtained from invasive hemody-namic monitoring and echocardiography.

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