Journal of the American College of Cardiology Vol. 45, No.

10, 2005
© 2005 by the American College of Cardiology Foundation ISSN 0735-1097/05/$30.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2005.01.046

Relationship Between B-Type

Natriuretic Peptides and Pulmonary
Capillary Wedge Pressure in the Intensive Care Unit
Paul R. Forfia, MD, Stanley P. Watkins, MD, J. Eduardo Rame, MD, Kerry J. Stewart, EDD,
Edward P. Shapiro, MD
Baltimore, Maryland
OBJECTIVES We examined whether B-type natriuretic peptides (BNP) can serve as noninvasive markers of
pulmonary capillary wedge pressure (PCWP) in the setting of critical illness.
BACKGROUND The BNP and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are highly correlated
with left ventricular (LV) filling pressures in patients with depressed LV systolic function.
However, their relationship to PCWP in a heterogeneous intensive care unit (ICU)
population has not been established.
METHODS We prospectively studied 40 patients in the ICU requiring invasive hemodynamic monitoring.
Hemodynamics were recorded simultaneously with blood sampling for BNP and NT-proBNP.
RESULTS The BNP (median 420 pg/ml) and NT-proBNP (median 3,304 pg/ml) levels were markedly
elevated, but weakly correlated with PCWP (BNP, r ⫽ 0.40, NT-proBNP, r ⫽ 0.32) and
other cardiac parameters. Peptide levels were approximately four-fold greater in patients with
impaired (estimated glomerular filtration rate [eGFR] ⬍60 ml/min) versus normal (eGFR
⬎60 ml/min) renal function, despite similar PCWP, cardiac index, and LV ejection fraction.
In addition, both BNP and NT-proBNP showed stronger correlations with PCWP in
patients with preserved (BNP, r ⫽ 0.58, NT-proBNP, r ⫽ 0.73) versus impaired renal
function (BNP, r ⫽ 0.48, NT-proBNP, r ⫽ 0.34). Interaction terms between eGFR and
BNP (p ⫽ 0.06) and NT-proBNP (p ⫽ 0.04) suggest that eGFR modulates the relationship
of these peptides to filling pressures.
CONCLUSIONS The BNPs are markedly elevated, yet show only weak correlations to PCWP in ICU patients
requiring invasive hemodynamic monitoring. Thus, a single value for BNP or NT-proBNP
may not be a clinically useful noninvasive marker of filling pressures in the critically ill patient.
This appears to be especially true in patients with impaired renal function. (J Am Coll
Cardiol 2005;45:1667–71) © 2005 by the American College of Cardiology Foundation

The B-type natriuretic peptide (BNP) and N-terminal (PAC) had been inserted for a clinical indication. Patients
pro-B-type natriuretic peptide (NT-proBNP) are co- with an acute myocardial infarction, a troponin I level ⬎1.0
secreted from the cardiac ventricles in response to stretch ng/ml, and those recovering from cardiac surgery or receiv-
and other non-mechanical stimuli (1,2). Both peptides are ing nesiritide were excluded. Informed consent was ob-
markers of left ventricular (LV) dysfunction, and elevated tained. The study was approved by the Johns Hopkins
levels aid in discriminating cardiac from non-cardiac dys- Institutional Review Board.
pnea (3). Peptide levels also correlate with LV filling Hemodynamics. Adequate position of the PAC was con-
pressures in patients with depressed systolic function (4,5). firmed by radiograph and hemodynamic waveform analysis.
However, it is unclear whether BNP or NT-proBNP are All PAC-derived hemodynamics were recorded at end
markers of pulmonary capillary wedge pressure (PCWP) in expiration, with PCWP adjusted for a positive end expira-
a population of critically ill patients with a broad range of tory pressure ⱖ10 cm H2O (6). Cardiac output was mea-
diagnoses and cardiac function. sured by thermodilution in triplicate. An echocardiogram
We conducted a prospective observational study examin- was performed the same day as the study. Left ventricular
ing the relationship between BNP and NT-proBNP and
dimensions, mass, wall stress, and left ventricular ejection
PCWP in critically ill patients requiring invasive hemody-
fraction (LVEF) were measured as previously described (7).
namic monitoring. We sought to determine whether these
Glomerular filtration rate was estimated using the
peptides can be used as noninvasive markers of pulmonary
method of Cockcroft and Gault, incorporating ideal body
congestion in this cohort.
weight (8). An estimated glomerular filtration rate (eGFR)
⬍60 ml/min defined impaired renal function (9).
METHODS
Blood sampling. Arterial blood was collected simultaneous
Study population. Adult intensive care units (ICUs) were with hemodynamic recordings and analyzed within 1 h. The
screened for patients in whom a pulmonary artery catheter BNP analysis was performed on whole blood using the
Triage BNP assay (Biosite Inc., San Diego, California) (3).
From the Division of Cardiology, Johns Hopkins Hospital, Baltimore, Maryland.
Manuscript received June 4, 2004; revised manuscript received October 7, 2004, The NT-proBNP analysis was performed on serum using a
accepted January 26, 2005. standard core laboratory assay (Roche Diagnostics, Basel,
1668 Forfia et al. JACC Vol. 45, No. 10, 2005
Natriuretic Peptides and Wedge Pressure in the ICU May 17, 2005:1667–71

Table 1. Clinical Characteristics and Hemodynamics of the

Abbreviations and Acronyms 40 Patients
BNP ⫽ B-type natriuretic peptide Clinical characteristics
CI ⫽ cardiac index Demographics
eGFR ⫽ estimated glomerular filtration rate Age, yrs (median; IQR) 62 (52; 73)
ICU ⫽ intensive care unit Men 22 (55)
IQR ⫽ interquartile range Women 18 (45)
LV ⫽ left ventricular White 28 (70)
LVEF ⫽ left ventricular ejection fraction Black 10 (25)
NT-proBNP ⫽ N-terminal pro-B-type natriuretic Other 2 (5)
peptide Unit
PAC ⫽ pulmonary artery catheter Cardiac intensive care unit 17 (43)
PCWP ⫽ pulmonary capillary wedge pressure Surgical intensive care unit 23 (57)
Diagnosis
Congestive heart failure 12 (30)
Sepsis or ARDS 12 (30)
Switzerland). Values above the upper limit of the BNP and Major abdominal surgery 9 (23)
NT-proBNP assays were reported as 5,000 and 70,000 Major vascular surgery 4 (10)
pg/ml, respectively. Samples run in duplicate (n ⫽ 7) varied Trauma 3 (8)
by 1%, with a correlation coefficient of 0.99. Intubated/mechanically ventilated 26 (65)
Pressors/inotropes 15 (38)
Statistical analysis. Values are expressed as the median and Intra-aortic balloon pump 2 (5)
interquartile range (IQR). Differences between medians Hemodynamic parameters
were detected by Wilcoxon rank-sum test with two-tailed p Heart rate, beats/min 83 (76, 108)
values of ⬍0.05. Because the natriuretic peptide data were RAP, mm Hg 10 (8, 13)
not normally distributed, log BNP and log NT-proBNP Mean PAP, mm Hg 29 (21, 35)
PCWP, mm Hg 14 (10, 22)
were used in the correlations and regression models. A CO, l/min 5.9 (4, 8.3)
multivariate linear regression model was used to ascertain CI, l/min/m2 3.1 (2.1, 4.2)
independent predictors of BNP and NT-proBNP. The SV, ml/beat 73 (48, 93)
interaction between BNP (and NT-proBNP) and eGFR on Systemic vascular resistance, dyne · sec · cm5 923 (723, 1,635)
the relationship to PCWP was tested in a regression model. Ejection fraction, % 50 (20, 60)
An interaction term was created by entering log BNP (and Clinical characteristic data are expressed as number of patients (%). Hemodynamic
data expressed as median (interquartile range).
log NT-proBNP) into the model as a continuous variable ARDS ⫽ acute respiratory distress syndrome; CI ⫽ cardiac index; CO ⫽ carbon
and eGFR as a binary variable, defined as normal (GFR monoxide; IQR ⫽ interquartile range; PAP ⫽ pulmonary artery pressure; PCWP ⫽
pulmonary capillary wedge pressure; RAP ⫽ right atrial pressure; SV ⫽ stroke
⬎60 ml/min) or abnormal (GFR ⬍60 ml/min). A p value volume.
⬍0.05 was considered significant. Statistical analyses were
performed using Stata software version 8.0 (College Station, PCWP and LVEF, eGFR remained a significant indepen-
Texas). dent predictor of both BNP (beta coefficient ⫺0.45, p ⫽
0.002) and NT-proBNP (beta coefficient ⫺0.56, p ⫽
RESULTS 0.001). Body mass index, vasopressors, mechanical ventila-
Population characteristics. Table 1 summarizes the base- tion, and hypoxemia (PO2/FiO2 ratio) did not affect natri-
line clinical characteristics and hemodynamics of this criti- uretic peptide levels (data not shown).
cally ill population. The median age was 62 years. Approx- Figure 2 demonstrates that natriuretic peptide levels were
imately two-thirds of patients were intubated and approximately four-fold higher in patients with impaired
mechanically ventilated. A similar proportion of patients versus normal renal function, despite no differences in
had renal insufficiency (75% acute, 25% chronic). The PCWP, cardiac index (CI), or LVEF. In addition, mean
majority of patients (68%) had preserved LV systolic func- wall stress did not differ between the two groups (GFR ⬎60
tion (LVEF ⱖ50%). Fourteen patients (35%) died while in ml/min, 181 g/cm2 vs. GFR ⬍60 ml/min, 175 g/cm2; p ⫽
the hospital. 0.20).
BNPs and hemodynamics. The concentrations of BNP Figure 3 displays the correlations of BNP and NT-
(median 420 pg/ml, IQR 197 to 1,740) and NT-proBNP proBNP to PCWP in the patients with normal and im-
(median 3,304 pg/ml, IQR 1,153 to 14,713) were markedly paired renal function. For both peptides, the slope of the
elevated. However, natriuretic peptide levels showed only regression lines increased, and the univariate correlations
weak correlations with PCWP (Fig. 1). Inspection of each with PCWP strengthened in patients with an eGFR ⬎60
scatterplot revealed wide variations in PCWP for any given ml/min versus an eGFR ⬍60 ml/min. A similar trend was
value of BNP and NT-proBNP. Both peptides also showed seen in the correlations between the natriuretic peptide and
weak but significant correlations with other central hemo- pulmonary artery pressure, CI, and LVEF when stratified
dynamic parameters, troponin levels, and inverse correla- by renal function (Table 3). The interaction term for BNP
tions with LVEF and eGFR (Table 2). After adjusting for (p ⫽ 0.06) strongly suggests, and for NT-proBNP (p ⫽
JACC Vol. 45, No. 10, 2005 Forfia et al. 1669
May 17, 2005:1667–71 Natriuretic Peptides and Wedge Pressure in the ICU

cardiac stretch, not pressure, and thus is more closely

coupled to hemodynamics in the failing versus non-failing
heart (4,10 –12). In addition, previous studies have excluded
critically ill patients, thus minimizing the contributions of
potentially important non-mechanical stimuli for BNP
release, such as neurohormonal activation and myocardial
ischemia, both of which occur commonly in the setting of
critical illness (13,14). Consistent with our results, a recent
study showed that BNP levels weakly correlated with
PCWP (r ⫽ 0.32, p ⫽ 0.02) in a mixed ICU cohort, with
the optimal cutoff for BNP ⬍60% specific for a PCWP ⬎15
mm Hg (15).
BNPs and renal function. Previous studies have shown
that natriuretic peptide levels correlate inversely with GFR
in chronic kidney disease (16,17). Investigators have postu-
lated that higher filling pressures and wall stress play an
important role in this cardiorenal link. However, in our
patients with renal failure (75% acute), natriuretic peptide
levels were massively elevated and could not be explained on
the basis of higher filling pressures, wall stress, or depressed
cardiac function. Moreover, natriuretic peptide levels
⬎1,000 pg/ml (BNP) and 10,000 pg/ml (NT-proBNP)
were more specific for a GFR ⬍60 (BNP, 92%; NT-
proBNP, 100%) than for a PCWP ⬎18 mm Hg (BNP,
Figure 1. Scatterplots showing the correlation between pulmonary capil-
42%; NT-proBNP, 60%).
lary wedge pressure (PCWP) and log B-type natriuretic peptide (BNP) To our knowledge, this study is the first to document
(top) and log N-terminal pro-B-type natriuretic peptide (NT-proBNP) such natriuretic peptide-hemodynamic dissociations in the
(bottom) in the overall cohort. Values in parentheses indicate raw BNP
and NT-proBNP values. setting of renal failure and suggests that renal function has
a more direct effect on circulating natriuretic peptide levels
0.04), confirms, that renal function modulates the strength than previously recognized. Moreover, the present study
of the relationship between the natriuretic peptides and highlights the important limitations of these peptides as
PCWP. hemodynamic markers in this context. Further study is
warranted to determine what factors account for the in-
DISCUSSION creased natriuretic peptide levels in renal failure (i.e., neu-
The present study demonstrates that natriuretic peptide
levels were markedly elevated, but weakly correlated with Table 2. Univariate Correlations (r) of Log BNP and Log
invasive hemodynamics, most notably PCWP, in the setting NT-proBNP With Hemodynamic and Other Parameters in the
of critical illness. Regression analysis revealed that the Overall Cohort (n ⫽ 40)
PCWP varied widely at any given BNP and NT-proBNP BNP NT-proBNP
concentration. Moreover, circulating concentrations of
Variable r p Value r p Value
BNP and NT-proBNP were profoundly influenced by the
presence of renal failure, independent of pulmonary conges- RAP 0.21 0.20 0.23 0.15
mPAP 0.42 0.008 0.38 0.02
tion or depressed cardiac function. Thus, evidence from the
PCWP 0.40 0.01 0.32 0.04
current study suggests that neither BNP nor NT-proBNP CI ⫺0.37 0.02 ⫺0.33 0.04
are reliable markers of pulmonary congestion in critically ill EF ⫺0.49 0.002 ⫺0.36 0.03
patients. GFR ⫺0.35 0.03 ⫺0.45 0.004
BNPs and hemodynamics. The relatively weak correla- Age 0.21 0.19 0.22 0.18
Troponin I 0.33 0.04 0.43 0.006
tions between BNP and NT-proBNP and PCWP in the
LV mass 0.31 0.10 0.13 0.52
current study are at odds with previous studies showing LVIDd 0.15 0.47 0.04 0.82
strong correlations between these peptides and LV filling LVIDs 0.23 0.26 0.13 0.50
pressures (4,5). However, in contrast to the current study, BNP ⫽ B-type natriuretic peptide; EF ⫽ ejection fraction; GFR ⫽ glomerular
previous studies have focused almost exclusively on patients filtration rate; LV ⫽ left ventricular; LVIDd ⫽ left ventricular diastolic diameter;
LVIDs ⫽ left ventricular systolic diameter; mPAP ⫽ mean pulmonary artery
with significant LV systolic dysfunction. This is an impor- pressure; NT-proBNP ⫽ N-terminal pro-B-type natriuretic peptide; other abbrevi-
tant distinction, as BNP release occurs as a direct result of ations as in Table 1.
1670 Forfia et al. JACC Vol. 45, No. 10, 2005
Natriuretic Peptides and Wedge Pressure in the ICU May 17, 2005:1667–71

Figure 2. Bar graphs showing B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) values (top), and pulmonary
capillary wedge pressure (PCWP), cardiac index (CI), and ejection fraction (EF) (bottom) in patients with an estimated glomerular filtration rate (eGFR)
⬎60 ml/min and an eGFR ⬍60 ml/min. Median values are shown in bold, with interquartile ranges shown in parentheses.

rohormonal activation vs. impaired clearance), as well as the eGFR fell just short of statistical significance in the PCWP
significance of acute versus chronic kidney disease in this regression, despite evidence that renal function affects the
paradigm. circulating levels and the hemodynamic associations of both
Study limitations. The relatively small sample size in our peptides. A potential methodologic limitation was the use of
study limited our ability to make more definitive conclusions the Cockcroft-Gault formula to estimate GFR, as opposed
about associations between the natriuretic peptide and to the Modification of Diet in Renal Disease formula for
hemodynamics and the modifying role of renal function. estimation of GFR (13). However, eGFRs derived from
This likely explains why the interaction term for BNP and both formulas were highly correlated in our dataset (r ⫽

Figure 3. Scatterplots showing the correlation between pulmonary capillary wedge pressure (PCWP) and log B-type natriuretic peptide (BNP) (A) and log
N-terminal pro-B-type natriuretic peptide (NT-proBNP) (B) in patients with an estimated glomerular filtration rate (eGFR) ⬎60 ml/min (closed squares)
and an eGFR ⬍60 ml/min (open squares).
JACC Vol. 45, No. 10, 2005 Forfia et al. 1671
May 17, 2005:1667–71 Natriuretic Peptides and Wedge Pressure in the ICU

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BNP NT-proBNP patterns of atrial natriuretic peptide and brain natriuretic peptide in
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Acknowledgment substances in the critically ill—a comparison between survivors and
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