BNP is Not Consistently BNP is Not Consistently Elevated in PEElevated in PE

Robert Bilkovski, M.D.Erik Kulstad, M.D.Scott Guth, M.D.

Jeff Bohmer, M.D.

Advocate Christ Medical CenterOak Lawn, IL

B-type (formerly brain-type) natriuretic peptide (BNP):– 32-amino acid polypeptide – discovered in porcine brain at Miyazaki

medical college in Kiyotake, Japan– reported in a letter to Nature in 1988

B-type (formerly brain-type) natriuretic peptide (BNP):– unlike ANP, which is contained in storage

granules and released with only minor stimuli, BNP is synthesized in bursts through high-turnover mRNA in response to ventricular volume expansion

Biological actions of BNP include:– natriuresis – diuresis – decreased blood pressure through vasodilatory

effects

Major source of BNP in humans is the cardiac ventricles.

Close correlation exists between the degree of ventricular overload and the secretion of BNP.

A rapid BNP fluorescence immunoassay is available (Biosite Diagnostics, San Diego, CA).

Became available at Christ Hospital in July, 2001.

Levels below 80 pg/mL have “reasonable” sensitivity in excluding heart failure.

Some controversy exists as to the need for additional diagnostic tests for CHF, as well as the true sensitivity of BNP.

Since left ventricular mass dominates, BNP elevations are typically predominated by left heart strain and overload.

During initial use, some patients at ACHMC were noted to have significant BNP elevations with pulmonary emboli, suggesting contribution from right ventricular source.

Limited prior descriptions of BNP levels in PE.– Maisel A. J. Cardiac Failure 2001;7(2):183-93.

(Suggested possibility of elevations to 300-600 pg/mL in PE.)

– Kurose M, Yoshimura M,Yasue H. Heart 1997;78(3):320-1.

(Single patient report, with elevation to 522 pg/mL in PE.)

– Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. J Am Coll Cardiol 2002;39(2):202-9.

(Three patients with PE and BNP of 200 to 300 pg/mL.)

– Tulevski, II, Hirsch A, Sanson BJ, et al. Thromb Haemost 2001;86(5):1193-6.

(BNP higher in 16 patients with PE than in 12 controls.)

– Tulevski, II, Groenink M, van Der Wall EE, et al. Heart 2001;86(1):27-30.

(BNP higher in 21 patients with RV overload from congenital heart disease compared to 7 controls.)

– Nagaya N, Nishikimi T, Okano Y, et al. J Am Coll Cardiol 1998;31(1):202-8.

(BNP higher in 26 patients with RV pressure overload [294 +/- 72] than in 18 patients with RV volume overload.)

– Smithline HA, Kline JA. Acad Emerg Med 2002;9(5):481.

(BNP is not elevated in 12 rats with latex-microsphere-induced pulmonary embolism compared to controls.)

A case series of 5 patients with PE and BNP elevations to 252, 353, 355, 432, and 570 pg/mL accumulated from our hospital.

Suggested possibility of using elevations in BNP as a screen for PE.

Study designed with null hypothesis of insignificant difference in BNP levels between patients with and without PE.

Obtained IRB approval in 2002 to prospectively evaluate BNP levels in patients with possible PE.

Convenience patient sample over a 3 month period in early 2003.

Inclusion Criteria:– Patients presenting to the ED with signs or

symptoms concerning for pulmonary embolism.– Age > 18.– Further diagnostic imaging procedure for work-

up of PE planned (V/Q scan, Doppler U/S, and/or CT angiogram).

Exclusion Criteria:– Prior history of heart failure– CAD – COPD– Valvular disease

Power estimates: – Limited by uncertainties in expected values of

BNP levels in our patient population.– Using data from prior observations, and

assuming an incidence of PE in study patients of 10%, we obtained an estimate of 20 patients needed to provide a power of 80% with a level of significance of 0.05 (NCSS/PASS)

Results:– Enrollment of 12 patients.– Two excluded due to lack of confirmatory

study, lack of BNP level.

Results:– Two had PE diagnosed by CT chest. – BNP levels in these two patients were 52

pg/mL and 82 pg/mL. – These levels were lower than the mean of

patients without PE, which was 284 pg/mL.

BNP Levels

0

500

1000

1500

2000

1 2 3 4 5 6 7 8

Patient

BNP (

pg/m

L) PE

No PE

Patients with PE:– 71 y.o. female with c/o SOB, CP.

BNP 52 CT chest: bilateral lower lobe PE with additional

RUL filling defects. Doppler U/S: +DVT

– 66 y.o. female with c/o 2 days right sided CP. BNP 82 CT chest: R main PA embolism.

Diagnoses and BNP levels (pg/mL) in the 8 patients without PE included:

new-onset CHF (1660) asthma exacerbation (305) atrial fibrillation (34) pericardial effusion (135) anxiety (11) biliary colic (22) diaphragmatic hernia (84) sleep apnea (28).

Results:– The highest level of BNP, 1660 pg/mL, was

found in our patient diagnosed with new-onset CHF.

Results:– If this patient is excluded, the mean BNP level

in the patients without PE decreases to 88 pg/mL, which remains marginally higher than in our patients diagnosed with PE.

Significant limitations exist in our power estimates due to poorly known variance, since wide variability of BNP levels in patients with PE from prior work complicates estimation of means and standard deviations.

Example using rough-estimate, parametric calculation:

N = 2(Z/2 + Z)2(2/2)

If =.05, =.20,

and =50, =100:

N = 4

If =100, =50

N = 62

Additional limitations:

– Gold standard of pulmonary artery angiogram not utilized to rule-out PE.

– Gold standard not utilized to confirm PE.

– Enrollment limited to convenience sample.

Conclusions:– Although underpowered, our study suggests

that BNP levels would not be expected to demonstrate sensitivity in screening for PE.

– Caution remains warranted when interpreting BNP levels in patients in whom PE is a diagnostic consideration.