Diagnostic

Update

BNP assays: Predicting the future of patients with heart failure By Susan K. Frazier, RN, PhD, and Elizabeth Kinkade Arthur, RN, ANP, MS

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Nearly 6 million Americans have heart failure and 550,000 new cases are diagnosed each year.1 The increasing incidence and prevalence of heart failure is attributed to the aging population and improved survival from other cardiovascular disorders such as coronary artery disease.2 Mortality rates for heart failure are high; one in five die within 1 year of diagnosis.1,2 Eighty percent of men and 70% of women under 65 years of age who have heart failure will die within 8 years of diagnosis. Survival is poorer in men than in women, but fewer than 15% of women survive longer than 8 to 12 years.1,2 Early detection of disease or decompensation is dependent on a rapid, accurate diagnosis, which is often difficult based solely on clinical presentation and physical assessment.2 Delayed recognition of heart failure or decompensation will result in treatment delays, worsening of myocardial function, and potentially death. The use of a rapid, sensitive, and specific diagnostic test for heart failure would be an asset to the clinician and help improve patient outcome. Evaluating B-type natriuretic peptide (BNP) can be useful in determining the probability of heart failure decompensation.3,4 BNP is a neurohormone released by the ventricles in response to fluid volume overload. BNP levels are consistently elevated with heart failure, but aren’t markedly elevated with some other noncardiac etiologies of dyspnea and fatigue like chronic obstructive pulmonary disease unless heart failure is a comorbidity.4,5 Studies have shown that BNP levels can be useful in differentiating heart failure from medical conditions in symptomatic patients, in medication management, and in predicting morbidity and mortality.6,7 Early detection of heart failure or decompensation can lead to lower healthcare costs by improving heart failure management

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and reducing hospital admissions. Most important, early detection will decrease morbidity and mortality and improve quality of life.

Natriuretic peptides Natriuretic peptides are hormones integral to the regulation of fluid volume and BP homeostasis. The natriuretic peptides include atrial natriuretic peptide (ANP), BNP, C-type natriuretic peptide (CNP), and urodilatin. In general, natriuretic peptides exhibit natriuretic (inhibiting renal sodium reabsorption) and diuretic (augmentation of sodium and water excretion) action, suppress the renin-angiotensin-aldosterone system and sympathetic nervous system, and produce arterial and venous dilation.8,9 Natriuretic peptides are primarily inactivated by neutral endoproteases enzymatic degradation after receptor binding.10 PreproANP, a precursor to active ANP, is produced in cardiac myocytes and stored primarily as granules. Release is stimulated by atrial stretch or increased atrial volume.8,9 Granular storage of this precursor molecule provides a rapid response to sudden increases in vascular volume. The precursor molecule is rapidly processed during release from the granules to form active ANP. Once activated, ANP has a short half-life and is rapidly removed from circulation. Thus, the effects, which are primarily natriuresis and diuresis, are rapid but shortlived, and volume and pressure homeostasis are maintained. BNP also is produced as a precursor molecule (preproBNP) primarily in ventricular myocytes; however, minimal quantities are stored in granules.8,9 Following stimulation by an increase in ventricular volume or pressure, the myocyte initiates production and release of the precursor molecule that’s then split into an inactive molecule, November l Nursing2009Critical Care l

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N-terminal proBNP (NT-proBNP), and BNP, the biologically active molecule.11 BNP and NT-proBNP are found in equal concentrations, but the half-life of NT-proBNP is longer, providing more stability in the concentration of this molecule. BNP levels increase more slowly than ANP and with a slightly longer half-life; natriuretic and diuretic effects persist for a longer time. Because of these characteristics, BNP has been identified as a “distress hormone” secreted in response to increased ventricular load or elevated intrachamber pressure.12 CNP and urodilatin are paracrine peptides that typically receive less attention. Paracrine substances influence adjacent cells. CNP is synthesized primarily by the endothelium and current evidence suggests that its actions focus on local vascular regulation.8,9,13 Specifically, CNP produces relaxation of vascular smooth muscle and inhibits the action of local angiotensin-converting enzyme (ACE). CNP also inhibits vascular growth, but has less diuretic or natriuretic effect. The stimulus for release of CNP hasn’t been clearly identified, but recently, researchers suggested that CNP release is stimulated by an increase in myocardial wall tension.13 Urodilatin is a natriuretic peptide produced by renal tubular cells. Its primary actions include natriuresis and diuresis. When synthesized and used pharmacologically, urodilatin has had a significant bronchodilator effect on central and peripheral airways that’s potentially useful in the management of asthma and dyspnea secondary to heart failure.8,14 Urodilatin also has been used to prevent or attenuate renal failure due to tubular ischemia and to manage renal failure after organ transplant (liver, cardiac, bone marrow) and decompensated heart failure.15-18 Synthetic forms of BNP (nesiritide) and urodilatin have been produced for pharmacologic use.

Using BNP as a diagnostic tool Brain natriuretic peptide concentration may be evaluated in plasma or whole blood by fluorescent immunoassay.11 In 2000, the FDA approved the Triage BNP Test, a rapid, point-of-care BNP analysis system. The specimen should be analyzed within 4 hours of sampling; however, plasma may be separated by centrifugation and stored at –20º C (-4º F) if testing must be delayed. The blood specimen is transferred from the collection tube to the www.nursing2009criticalcare.com

Normal ranges for plasma BNP and NT-proBNP21,45 BNP Age

Women

Men

45 to 54

8 to 73 pg/mL

4 to 40 pg/mL

55 to 64

10 to 93 pg/mL

5 to 52 pg/mL

65 to 74

13 to 120 pg/mL

7 to 67 pg/mL

75 to 83

16 to 155 pg/mL

9 to 86 pg/mL

Age

Women

Men

45 to 59

61 to 164 pg/mL

28 to 100 pg/mL

60 and up

86 to 225 pg/mL

53 to 172 pg/mL

NT-proBNP

Triage BNP panel, which is inserted into the meter. Results are usually available within 15 to 20 minutes. The Triage BNP Test assesses BNP levels within 5 to 5,000 pg/mL; measured values have been found to be linear throughout this range. Analytical sensitivity, the lowest detectable BNP concentration, is less than 5 pg/mL. The precision of the measure or coefficient of variation ranges between 8.8% and 12.2%. There is a near-perfect association between measures made testing whole blood and those made testing plasma. Lab and point-of-care testing is now available for NT-proBNP.11 One assay can measure NTproBNP concentrations from 60 to 3,000 pg/mL, and is highly correlated with the lab assay.19 Results are available in 12 minutes. Values above and below the stated range aren’t measured, but are indicated as being above or below the limits of the equipment. BNP and NT-proBNP concentrations increase with age and are higher in women than in men, so age and gender must be considered in the interpretation of BNP values (see Normal ranges for plasma BNP and NT-proBNP).20,21 In a study of patients presenting with dyspnea or peripheral edema, the use of BNP values improved the diagnostic accuracy for heart failure by 21% when compared with practitioner diagnosis based solely on physical assessment.22 Studies November l Nursing2009Critical Care l

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Diagnostic

Update

have measured BNP concentration in dyspneic patients presenting to the ED to determine whether dyspnea was due to pulmonary disease or heart failure.20,23-25 A BNP concentration cutoff value of 94 pg/mL provided a sensitivity of 86%, specificity of 98%, and accuracy of 91%; a BNP level of 300 pg/mL had a sensitivity of 88%, specificity of 87%, and accuracy of 88%.23-25 In the Breathing Not Properly Multinational Study, a BNP concentration of 100 pg/mL differentiated dyspnea due to heart failure with a sensitivity of 90%.24 This concentration of BNP was also able to differentiate systolic heart failure with a sensitivity of 95%, but sensitivity was only 66% when attempting to differentiate systolic from diastolic heart failure in this group. Based on studies that evaluated the efficacy of BNP assays in the diagnosis of heart failure, a cut-off value of 100 pg/mL is recommended by the manufacturer of the Triage BNP Test, so patients who present with dyspnea and a BNP level less than 100 pg/mL may be rapidly evaluated for diagnoses other than heart failure. BNP analysis has also been used as a prognostic marker in cardiac patients.26-31 For example, at the time of diagnosis, BNP concentrations that exceed 480 pg/mL are predictive of death or hospitalization due to heart failure within the next 6 months.26 BNP concentrations have also been highly predictive of left ventricular ejection fraction and functional capacity in patients with heart failure.27,28 BNP concentration has been identified as a powerful, independent predictor of death or hospital readmission following hospitalization for decompensated heart failure.29 Additionally, BNP concentrations measured during acute coronary syndromes independently predict mortality, heart failure, and the occurrence of a new myocardial infarction.30 More recently, BNP values have been found to predict significant rejection in cardiac transplant recipients.31

Nursing implications The use of BNP assays to evaluate patients with dyspnea may provide clinicians with an opportunity for early detection of heart failure. Using a rapid BNP test in the primary care clinic when a patient presents with symptoms potentially related to heart failure will speed diagnosis and treat18

ment. A test showing an elevated BNP concentration might ensure that the patient receives timely additional diagnostic testing with echocardiography or cardiac catheterization. If heart failure is diagnosed in early stages, patients may begin making lifestyle changes that could affect the course of the disease, and early diagnosis will also equate to earlier pharmacologic intervention using heart failure guidelines.32 The high negative predictive value of the test indicates the chief use would be to rule out heart failure in suspected cases when normal BNP concentrations are measured.5 BNP measures can also detect decompensation of chronic heart failure. Early recognition and timely management in the clinical setting may reduce the need for emergent care and hospital admission and may decrease the length of stay when hospitalization is needed.33

Monitoring status Because BNP levels increase with heart failure progression and are strongly correlated to patient outcomes, BNP levels may serve as a guide to the severity of heart failure and the efficacy of management. Both baseline and change in BNP (increase or decrease) are important determinants of subsequent morbidity and mortality.34 Researchers evaluated the diagnostic and prognostic value of NT-proBNP in older adults with acute dyspnea, and found that plasma NTproBNP levels were associated with disease severity and were an independent predictor of mortality.7 Another study found that a greater percentage reduction in BNP after treatment for decompensated heart failure was associated with longer event-free survival.34 In another study, serial measures of BNP every 2 to 4 hours were made over a 2- to 3-day time period in patients admitted with decompensated heart failure. Researchers found a strong correlation between decreasing pulmonary capillary wedge pressures and BNP level.35 Although this was an acute situation and these investigators followed BNP over the very short term, there are implications for use of BNP levels in evaluating the response to heart failure management. In a study of 325 patients presenting to the ED with dyspnea, BNP was a predictive marker of future cardiac events—rising BNP levels were

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associated with progressively worse prognosis.26 In fact, patients with BNP levels greater than 480 pg/mL had a 51% 6-month cumulative probability of a heart failure event (death, hospital admission, or repeat ED visit). Alternatively, patients with BNP levels less than 230 pg/mL had an excellent prognosis with only 2.5% incidence of heart failure endpoint. Increased concentrations of BNP have independently identified heart failure patients who had a poor prognosis, using death as the endpoint. These data suggest BNP should be routinely used to evaluate heart failure patients, with high BNP levels indicating the need for more aggressive treatment.36,37 Evaluating BNP measures on hospital admission, on discharge, and a few weeks after discharge can provide important information about patient prognosis. Patients with low BNP levels on admission, discharge, and follow-up, or those with reduced BNP after therapy, were significantly less likely to be rehospitalized or die within 6 months.38

Management of therapy BNP levels may be followed over time.39 In a study using BNP measures to optimize medical management of patients admitted with decompensated heart failure, one patient group received standard clinician-guided therapy while another group received optimized pharmacologic regimens (including ACE inhibitor, diuretic, digoxin, additional diuretic, angiotensin receptor blocker, and vasodilator in a stepwise fashion) based on BNP concentration.5 After 6 months, the BNP-guided group had fewer total cardiovascular events (death, hospital admission, heart failure decompensation) than the clinician-guided group. Their data demonstrated that circulating BNP concentration, as well as total cardiovascular events, were reduced by intensification of drug therapy. Further research is needed to determine the BNP levels appropriate for initiating specific drugs at specific dosages. The Valsartan Heart Failure Trial (Val-HeFT) study of about 4,300 patients showed that valsartan produced a sustained reduction in BNP in patients with heart failure.40 This study determined that not only was BNP a strong predictor of all-cause mortality and first morbid event, but also that changes in BNP over time corresponded www.nursing2009criticalcare.com

to changes in morbidity and mortality. Other researchers have found the use of a BNP-guided approach to medication titration targeted to reduce BNP levels to a predetermined level has been associated with a significant reduction in cardiovascular events compared with the clinically guided approach.39 Similar outcomes have been found by researchers using ACE inhibitors and spironolactone in combination.41 Results from the Randomized Aldactone Evaluation Study indicate a place in the optimization of medication management for monitoring BNP. Heart failure patients who received spironolactone had decreased BNP levels, which the authors suggested may be due to changes in left ventricular filling pressures or improved ventricular compliance.42 Neurohormonal profiling may guide introduction of beta-receptor antagonists in heart failure treatment for patients with ischemic left ventricular dysfunction.43 For example, titration of carvedilol, a nonselective beta-receptor blocker, reduced mortality and improved heart failure in those patients who demonstrated higher pretreatment BNP levels. In contrast, another study concluded that BNPguided therapy wasn’t superior to symptomguided therapy for heart failure, although survival time free of hospitalization for heart failure (a secondary outcome) was greater in the BNPguided group.44 More research is needed to clearly establish the efficacy of BNP-guided therapy.

An evolution The use of BNP testing for the management of cardiac disease is evolving. Aside from using it as a diagnostic or prognostic tool, or in the pharmacologic management of heart failure, evaluation of BNP level could even assist healthcare providers when determining whether to discharge a patient. Patients with heart failure generate significant healthcare costs caused by intensive outpatient management, frequent ED visits, and inpatient admissions. The recidivism rate is high, with onethird of patients readmitted each year. Hospital discharges for heart failure rose 171% between 1979 (400,000) and 2005 (1.08 million).1 In 2008, direct and indirect costs of heart failure for Americans was $34.8 billion; projected costs for 2009 are November l Nursing2009Critical Care l

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$37.2 billion.1 A test that can quickly and accurately diagnose a disease and assist in monitoring patients’ treatment efficacy and disease stage, as well as reduce healthcare costs, clearly should be considered useful in caring for patients with heart failure. ❖ REFERENCES 1. American Heart Association. Heart Disease and Stroke Statistics— 2009 Update. Dallas, TX: American Heart Association; 2009. 2. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence and survival with heart failure. N Engl J Med. 2002;347(18):1397–1402. 3. Collins SP, Ronan-Bentle S, Storrow AB. Diagnostic and prognostic usefulness of natriuretic peptides in emergency department patients with dyspnea. Ann Emerg Med. 2003;41(4):532–545. 4. Rogers RK, Stoddard GJ, Greene T, et al. Usefulness of adjusting for clinical covariates to improve the ability of B-type natriuretic peptide to distinguish cardiac from noncardiac dyspnea. Am J Cardiol. 2009;104(5):689–694. 5. Troughton R, Frampton C, Yandle T, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000;(9210)355:1126–1130. 6. Betti I, Castelli G, Barchielli A, et al. The role of N-terminal PRO-brain natriuretic peptide and echocardiography for screening asymptomatic left ventricular dysfunction in a population at high risk for heart failure. The PROBE-HF study. J Card Fail. 2009;15(5): 377–384. 7. Reny JL, Millot O, Vanderecamer T, et al. Admission NT-proBNP levels, renal insufficiency and age as predictors of mortality in elderly patients hospitalized for acute dyspnea. Eur J Intern Med. 2009;20(1):14–19. 8. Lee CY, Burnett JC Jr. Natriuretic peptides and therapeutic applications. Heart Fail Rev. 2007;12(2):131–142. 9. Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM. Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications. Handb Exp Pharmacol. 2009;191: 341–366. 10. Omland T, Hagve TA. Natriuretic peptides: physiologic and analytic considerations. Heart Fail Clin. 2009;5(4):471–487. 11. Prontera C, Emdin M, Zucchelli GC, Ripoli A, Passino C, Clerico A. Analytical performance and diagnostic accuracy of a fully-automated electrochemiluminescent assay for the N-terminal fragment of the pro-peptide of brain natriuretic peptide in patients with cardiomyopathy: comparison with immunoradiometric assay methods for brain natriuretic peptide and atrial natriuretic peptide. Clin Chem Lab Med. 2004;42(1):37–44. 12. Maisel AS. The diagnosis of acute congestive heart failure: role of BNP measurements. Heart Fail Rev. 2003;8(4):327–334. 13. Palmer SC, Prickett TC, Espiner EA, Yandle TG, Richards AM. Regional release and clearance of C-type natriuretic peptides in the human circulation and relation to cardiac function. Hypertension. 2009;54:612–618. 14. Forssmann K, Meyer M, Forssman WG. Urodilatin. In: Hansel TT, Barnes PJ, eds. New drugs for asthma, allergy and COPD. Prog Respir Res. 2001;31:81–84. 15. Lüss H, Mitrovic V, Seferovic PM, et al. Renal effects of ularitide in patients with decompensated heart failure. Am Heart J. 2008;155(6):1012e1–1012e8. 16. Cedidi C, Kuse ER, Meyer M, et al. Treatment of acute postoperative renal failure after liver and heart transplantation. Clin Investig. 1993;71(6):435–436. 17. Cedidi C, Meyer M, Kuse ER, et al. Urodilatin: a new approach

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for the treatment of therapy-resistant acute renal failure after liver transplantation. Eur J Clin Invest. 1994;24(9):632–639. 18. Laws HJ, Kropp S, Meyer M, Forssmann WG, Burdach S. Treatment of acute renal failure with urodilatin after unrelated bone marrow transplantation. Bone Marrow Transplant. 1995;16(2): 307–310. 19. Alehagen U, Janzon M. A clinician’s experience of using the Cardiac Reader NT-proBNP point-of-care assay in a clinical setting. Eur J Heart Fail. 2008;10(3):260–266. 20. Lainchbury JG, Campbell E, Frampton CM, Yandle TG, Nicholls MG, Richards AM. Brain natriuretic peptide and N-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath. J Am Coll Cardiol. 2003;42(4): 728–735. 21. Galasko GI, Lahiri A, Barnes SC, Collinson P, Senior R. What is the normal range for N-terminal pro-brain natriuretic peptide? How well does this normal range screen for cardiovascular disease? Eur Heart J. 2005;26(1):2269–2276. 22. Wright SP, Doughty RN, Pearl A, et al. Plasma amino-terminal pro-brain natriuretic peptide and accuracy of heart-failure diagnosis in primary care. A randomized, controlled trial. J Am Coll Cardiol. 2003;42(10):1793–1800. 23. Logeart D, Saudubray C, Beyne P, et al. Comparative value of Doppler echocardiography and b-type natriuretic peptide assay in the etiologic diagnosis of acute dyspnea. J Am Coll Cardiol. 2002;40(10):1794–1800. 24. Maisel AS, McCord J, Nowak RM, et al. Bedside b-type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational study. J Am Coll Cardiol. 2003;41(11): 2010–2017. 25. Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of a rapid b-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol. 2002;39(2): 202–209. 26. Harrison A, Morrison LK, Krishnaswamy P, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Ann Emerg Med. 2002; 39(2):131–138. 27. Moertl D, Berger R, Struck J, et al. Comparison of midregional pro-atrial and B-type natriuretic peptides in chronic heart failure: influencing factors, detection of left ventricular systolic dysfunction, and prediction of death. J Am Coll Cardiol. 2009;53(19): 1783–1790. 28. Krüger S, Graf J, Kunz D, Stickel T, Hanrath P, Janssens U. Brain natriuretic peptide levels predict functional capacity in patients with chronic heart failure. J Am Coll Cardiol. 2002;40(4): 718–722. 29. Logeart D, Thabut G, Jourdain P, et al. Predischarge b-type natriuretic peptide assay for identifying patients at high risk of readmission after decompensated heart failure. J Am Coll Cardiol. 2004;43(4):635–641. 30. Richards AM, Nicholls MG, Espiner EA, et al. B-type natreiuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation. 2003;107(22):2786–2792. 31. Kittleson MM, Skojec DV, Wittstein IS, et al. The change in Btype natriuretic peptide levels over time predicts significant rejection in cardiac transplant recipients. J Heart Lung Transplant. 2009; 28(7):704–709. 32. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. Circulation. 2009; 119(14):e391-e479. 33. Crook JA, Woody FA. Technology Update: Rapidly identifying CHF with POC advances. Nurs Manag. 2003;34(1):48–49. 34. Dhaliwal AS, Deswal A, Pritchett A, et al. Reduction in BNP levels with treatment of decompensated heart failure and future clinical events. J Card Fail. 2009;15(4):293–299.

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35. Kazanegra R, Cheng V, Garcia A, et al. A rapid test for B-type natriuretic peptide (BNP) correlates with failing wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail. 2001;7(1):21–29.

tor therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: randomized comparison of the hemodynamic and neuroendocrine effects of tailored versus empirical therapy. Am Heart J. 1999;138(6 Pt. 1):1126–1132.

36. Bettencourt P, Ferriera A, Dias P. Predictors of prognosis in patients with stable mild to moderate heart failure. J Card Fail. 2000; 6(4):306–313.

42. Rousseau MF, Gurne O, Duprez D, et al. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure. J Am Coll Cardiol. 2002;40(9):1596–1601.

37. Maeda K, Tsutamoto T, Wada A. High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk factors for morbidity and mortality in patients with congestive heart failure. J Am Coll Cardiol. 2000; 36(5):1587–1593.

43. Richards AM, Doughty R, Nicholls MG, et al. Neurohumoral prediction of benefit from carvedilol in ischemic left ventricular dysfunction. Circulation. 1999;99(6):786–792.

38. Faggiano P, Valle R, Aspromonte N, et al. How often we need to measure brain natriuretic peptide (BNP) blood levels in patients admitted to the hospital for acute severe heart failure? Role of serial measurements to improve short-term prognostic stratification. Int J Cardiol. 2009;epub ahead of print. 39. Felker GM, Hasselblad V, Hernandez AF, O’Connor CM. Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials. Am Heart J. 2009;158(3):422–430. 40. Latini R, Masson S, Anand I, et al. Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure. The valsartan heart failure trial (ValHeFT). Circulation. 2002;106(19):2454–2458. 41. Murdock D, McDonagh T, Byrne J, et al. Titration of vasodila-

44. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs. symptomguided heart failure therapy: the trial of intensified vs standard medical therapy in elderly patients with congestive heart failure (TIME-CHF) randomized trial. JAMA. 2009;301(4):383–392. 45. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol.2003;40(5): 976–982. Susan K. Frazier is an associate professor and a codirector of the RICH Heart Program at the University of Kentucky in Lexington. Elizabeth Kinkade Arthur is a nurse practitioner at the James Cancer Hospital and Research Institute, part of the Ohio State University Medical Center at Columbus. Adapted and updated from Kinkade E, Frazier SK. BNP assays: predicting the future of CHF patients. Nurse Practitioner. 2006;31(12):36–41.

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