Diagnostic utility of B-type natriuretic peptide in critically ill patients with pulmonary edema: a prospective cohort study
- Joseph E Levitt†1Email author,
- Ajeet G Vinayak†2,
- Brian K Gehlbach3,
- Anne Pohlman3,
- William Van Cleve4,
- Jesse B Hall3 and
- John P Kress3
© Levitt et al.; licensee BioMed Central Ltd. 2008
Received: 21 June 2007
Accepted: 14 January 2008
Published: 14 January 2008
Distinguishing pulmonary edema due to acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) from hydrostatic or cardiogenic edema is challenging in critically ill patients. B-type natriuretic peptide (BNP) can effectively identify congestive heart failure in the emergency room setting but, despite increasing use, its diagnostic utility has not been validated in the intensive care unit (ICU).
We performed a prospective, blinded cohort study in the medical and surgical ICUs at the University of Chicago Hospitals. Patients were eligible if they were admitted to the ICU with respiratory distress, bilateral pulmonary edema and a central venous catheter suggesting either high-pressure (cardiogenic) or low-pressure (ALI/ARDS) pulmonary edema. BNP levels were measured within 48 hours of ICU admission and development of pulmonary edema and onward up to three consecutive days. All levels were drawn simultaneously with the measurement of right atrial or pulmonary artery wedge pressure. The etiology of pulmonary edema – cardiogenic or ALI/ARDS – was determined by three intensivists blinded to BNP levels.
We enrolled a total of 54 patients (33 with ALI/ARDS and 21 with cardiogenic edema). BNP levels were lower in patients with ALI/ARDS than in those with cardiogenic edema (496 ± 439 versus 747 ± 476 pg/ml, P = 0.05). At an accepted cutoff of 100 pg/ml, specificity for the diagnosis of ALI/ARDS was high (95.2%) but sensitivity was poor (27.3%). Cutoffs at higher BNP levels improved sensitivity at considerable cost to specificity. Invasive measures of filling pressures correlated poorly with initial BNP levels and subsequent day BNP values fluctuated unpredictably and without correlation with hemodynamic changes and net fluid balance.
BNP levels drawn within 48 hours of admission to the ICU do not reliably distinguish ALI/ARDS from cardiogenic edema, do not correlate with invasive hemodynamic measurements, and do not track predictably with changes in volume status on consecutive daily measurements.
Early implementation of a lung protective ventilation strategy can improve survival from acute lung injury and the acute respiratory distress syndrome (ALI/ARDS) . However, a recent survey of intensive care units (ICUs) found that a lack of physician recognition of ALI/ARDS was a major barrier to the initiation of lung-protective ventilation . Attributing pulmonary edema to volume overload or congestive heart failure may explain some of this underdiagnosis. The American–European Consensus Conference definition of ALI/ARDS requires the exclusion of left atrial hypertension . However, advanced age and comorbidities can make this difficult in critically ill patients. Pulmonary artery catheters reliably measure left atrial pressure, but placement can be time-consuming and a recent multicenter randomized trial found no benefit with their routine use in ALI/ARDS . Echocardiography provides noninvasive assessment of left ventricular dysfunction but requires an experienced operator and is limited by lack of universal accessibility and added cost.
B-type natriuretic peptide (BNP), a rapidly-assayed, serum biomarker, has been found to be effective in distinguishing congestive heart failure (CHF) from other causes of dyspnea in the emergency or urgent care setting [5–7]. Ease, low cost, and objectivity have led to widespread incorporation of BNP into the clinical evaluation of CHF. Anecdotal experience also suggests an increasing use of BNP by physicians in the ICU; however, although extrapolation to other clinical settings is tempting, appropriate validation is lacking.
Jefic and colleagues found that levels of BNP correlated with severity of left ventricular dysfunction but did not reliably distinguish high from low pulmonary capillary wedge pressure (PCWP) causes of respiratory failure in critically ill patients . In addition, BNP levels can be markedly, but similarly, increased in both cardiogenic and septic shock despite significant differences in hemodynamic measures [9–11]. Conversely, Rana and colleagues found that a BNP level of less than 250 pg/ml had a high specificity for ALI/ARDS and was comparable to measuring PCWP and superior to troponin levels and echocardiography for distinguishing between ALI/ARDS and cardiogenic edema .
There are many possible explanations for these discrepancies. Coexisting cardiac and other organ dysfunction, rapid changes in volume status, variable bioavailability  and burst synthesis of BNP [14, 15] may all confound interpretation of BNP levels in critically ill patients. Given the potential for confounding by coexisting or overlapping conditions of lung injury and hydrostatic pulmonary edema, we performed a prospective clinical trial of the diagnostic utility of BNP in selected patients with convincing evidence of either ALI/ARDS or cardiogenic pulmonary edema.
Materials and methods
This prospective, blinded cohort study was approved by the Institutional Review Board and performed in the medical and surgical ICUs at the University of Chicago Hospitals. Patients were eligible for enrollment on the following criteria: if they were admitted to an ICU; if they had a chest radiograph consistent with bilateral pulmonary edema on the morning of enrollment, if they had a partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio of less than 300; and if they had a pulmonary artery catheter or a central venous catheter and current echocardiogram. Enrollment and first BNP sampling were required within 48 hours of the first qualifying chest radiograph performed in an ICU.
To aid in definitive classification, only patients identified during screening by a study physician as having clear clinical evidence of high-pressure (cardiogenic) or low-pressure (ALI/ARDS) pulmonary edema were enrolled, with the exclusion of ambiguous, intermediate cases. In addition to clinical history, enrollment to the cardiogenic edema cohort required either (1) a PCWP of more than 20 mmHg or (2) a right atrial pressure (RAP) of more than 14 mmHg with a current echocardiogram documenting (on final report by readers blinded to patient's study classification and BNP level) new or worsening left ventricular systolic or diastolic dysfunction (LVD). Echocardiograms were required during the current admission up to enrollment. LVD was considered 'new' in patients without a previous history of CHF or with a previous echocardiogram documenting normal left ventricular function and 'worsened' only when a previous echocardiogram was available for direct comparison. Conversely, enrollment to the ALI/ARDS cohort required a PCWP of less than 16 mmHg or a RAP of less than 10 mmHg and no echocardiographic evidence of new or worsening LVD. Invasive hemodynamic pressure tracings were recorded simultaneously with blood sampling for BNP levels. Readings were taken at end-expiration using airway pressure waveform tracings as recommended by the ARDS Clinical Trials Network .
Final classification as ALI/ARDS or cardiogenic edema was done independently by a jury of three experienced critical care attending physicians blinded to BNP results and to the patient's enrollment cohort. Jurors reviewed information on clinical course and response to treatment up to discharge in addition to daily waveform tracings of invasive pressure measurements, echocardiogram reports, and chest radiographs. Discrepant cases were classified by majority opinion.
Patients with renal failure requiring dialysis, patients with intracranial hemorrhage or elevated intracranial pressure, patients with a history of cardiac surgery within 2 months, patients on a nesiritide infusion, pregnant women, and patients with persistent symptoms for greater than 2 weeks before admission were excluded.
Informed consent was obtained from each patient or surrogate decision maker. Baseline characteristics that were collected included the following: patient demographics, serum creatinine, Acute Physiology and Chronic Health Evaluation II (APACHE II) severity of illness score , lung injury score , requirement for vasoactive drugs (dobutamine, milrinone, vasopressin, norepinephrine, or dopamine) at the time of blood draw on day 1, and need for mechanical ventilation (noninvasive positive pressure ventilation or mechanical ventilation by means of an endotracheal tube or tracheostomy). A presence of right heart dysfunction was defined as a mean pulmonary artery pressure of more than 20 mmHg or echocardiographic evidence of mild or worsening pulmonary hypertension with right ventricular dysfunction or dilatation .
Measurement of BNP occurred immediately after enrollment (within 48 hours of qualifying chest radiograph and ICU admission) and then daily for a total of 3 days. Subsequent samples were not available for patients who were transferred from the ICU, who had discontinuation of invasive venous monitoring or who were started on dialysis or a nesiritide infusion during the 3-day study period. Waveform tracings from central venous and pulmonary artery catheters were recorded simultaneously with the time of blood draws. Blood samples were collected in tubes containing potassium EDTA and were measured with a rapid fluorescence immunoassay (Triage; Biosite Diagnostics, San Diego, CA, USA) [5, 6].
Data were analysed with GraphPad Prism (GraphPad, San Diego, CA, USA) software. A Student's t test or Mann–Whitney U test was used to assess differences between continuous variables as appropriate. Dichotomous, categorical variables were analyzed by Fisher exact or χ2 tests. Correlation between continuous variables was assessed by Pearson correlation coefficients. Data are presented as means ± standard deviations and medians with interquartile ranges where appropriate. Despite a positive skew in distribution of BNP levels, similar results were found between analyses of log-transformed and raw BNP values, and only comparisons of raw BNP values are reported. Receiver operating characteristic (ROC) curves generated by Analyse-It Clinical Laboratory (Leeds, UK) were used to assess the utility of BNP as a diagnostic tool.
Baseline characteristics and invasive hemodynamics by edema classification
60 ± 3
59 ± 5
Female sex, n (percentage)
74.7 ± 4.9
91.7 ± 6.8
Race, n (percentage)
APACHE II score
20.7 ± 1.1
20.2 ± 1.2
Lung injury score
2.6 ± 0.1
2.6 ± 0.2
1.2 ± 0.1
2.2 ± 0.3
Vasoactive druga use, n (percentage)
Mechanical ventilation, n (percentage)
RHDb, n (percentage)
LVDc, n (percentage)
5.9 ± 6.3
15.2 ± 5.7
PCWP, mmHg (n = 5 and 9)
6.8 ± 2.5
21.4 ± 5.5
Mean BNP values and receiver operating characteristic analysis by subgroup
Serum creatinine < 3.0 mg/dl
Excluding the four ALI/ARDS with LVDa
Serial BNP measurements by edema classification
Direction of BNP change
n (ΔBNP, pg/ml)
Days 1 to 2
17 (254 ± 302)
5 (228 ± 287)
9 (-246 ± 178)
8 (-252 ± 208)
26 (73 ± 339)
17 (-52 ± 290)
Days 2 to 3
9 (143 ± 200)
5 (396 ± 132)
11 (-191 ± 187)
7 (-160 ± 142)
24 (-34 ± 231)
15 (57 ± 281)
In this prospective, blinded cohort study, we found that BNP levels did not reliably distinguish ALI/ARDS from cardiogenic causes of pulmonary edema despite efforts to exclude patients with possible overlapping conditions. In addition, BNP levels correlated poorly with simultaneous invasive measures of RAP and PCWP. Serial measurements over a 3-day period did not improve performance because changes in BNP levels did not correlate with changes in invasive measures of filling pressures and did not differ in direction or magnitude between patients with ALI/ARDS and those with cardiogenic edema.
Our results are similar to those of other investigators who found that BNP levels did not discriminate between cardiogenic and septic shock [9–11] and between high and low PCWP causes of pulmonary edema . This may be due to increased levels of BNP related to myocardial dysfunction of sepsis or direct effect of inflammatory mediators on myocytes [19, 20]. In addition, BNP levels are known to be elevated in ARDS, in part as a result of acute right heart dysfunction [21, 22]. Right heart dysfunction was a common occurrence in our cohort (48% and 71% of the ALI/ARDS and CHF cohorts, respectively). Increased stretch of the right ventricle and right atrium may be a source of BNP release in critically ill patients, independently of left ventricular filling pressures. In addition, in the previous studies of shock, there were significant differences in PCWP values between cardiac and non-cardiac etiologies; however, the 'low' PCWP values were markedly abnormal (means of 16 ± 4 and 18 ± 7 mmHg, respectively) [10, 11].
We sought to avoid this confounder by including only ALI/ARDS patients with a PCWP of less than 16 mmHg and cardiogenic edema patients with a PCWP of more than 20 mmHg. In our study, mean RAP and PCWP were 5.9 ± 5.7 and 6.8 ± 2.5 mmHg, respectively, in the ALI/ARDS patients, in contrast with 15.2 ± 5.7 and 21.4 ± 5.5 mmHg in the CHF patients. However, this wide separation in filling pressures between cohorts did not improve the discriminatory function of BNP in our study.
We did not specifically study the presence or impact of left ventricular diastolic dysfunction in our cohorts. Given the low prevalence of pulmonary artery catheters in our ALI/ARDS patients (5 of 33), it is possible that our some of our ALI/ARDS patients with high BNP levels were actually misclassified because of under-recognition of diastolic dysfunction and occult left atrial hypertension. However, all patients without a pulmonary artery catheter required a current echocardiogram to be eligible for enrollment. We believe that our reference standard for edema classification – independent adjudication by three blinded experienced intensivists on retrospective review of all relevant data (including echocardiogram reports, chest radiographs, invasive pressure tracings and response to therapy) – although imperfect, is the most valid and clinically relevant standard available. Similar reference standards have been used by Maisel and colleagues , in their landmark paper demonstrating the utility of BNP for diagnosing heart failure in the emergency room, and by Rana and colleagues .
Rana and colleagues, using methodology similar to ours to evaluate the utility of BNP in distinguishing patients with ALI from patients with CHF, found the AUC of their ROC to be 0.71 . Using a BNP level of less than 250 pg/ml to diagnose ALI/ARDS had good specificity (90%) and modest sensitivity (40%), with positive and negative likelihood ratios of 4.0 and 0.67, respectively. When restricted to patients without renal insufficiency (41% of their cohort) the AUC improved to 0.82. When limited to patients without renal insufficiency and ALI/ARDS patients without concomitant cardiac dysfunction (only 25% of their total cohort), the AUC improved to 0.86. In contrast, our study, which by design excluded ALI patients with coexisting cardiac dysfunction, found an AUC of 0.67, and excluding patients with a serum creatinine of more than 3.0 mg/dl had a minimal impact on performance (AUC 0.70). However, serum creatinine may not always accurately reflect creatinine clearance, and excluding patients on the basis of a more sensitive measure of renal dysfunction (such as a creatinine clearance of less than 60 ml/min, as used by Rana and colleagues ) might have improved the performance of BNP in our study.
Serum creatinine and weight were significantly greater in the cardiogenic edema cohort and may have biased our findings. However, by multivariate linear regression (modeling BNP levels on edema type, weight, and creatinine) there was a trend toward a positive association of BNP and creatinine (P = 0.09) and a negative association of weight and BNP (P = 0.08) but no association of BNP and edema type (P = 0.61), suggesting that these confounders do not explain the poor diagnostic utility of BNP in our study (data not shown). The median time from recognition of pulmonary edema to measuring BNP levels was 3 hours (interquartile range 0.5 to 14) in the study by Rana and colleagues. We did not specifically record time to BNP draw, but our protocol allowed enrollment up to 48 hours after the presence of a qualifying chest radiograph and ICU admission. Importantly, while we allowed up to 48 hours for enrollment and first blood draw, all BNP and hemodynamic measurements were made simultaneously. This protocol difference probably accounts for the better performance in the Rana study. Similarly, other authors have found excellent sensitivity and specificity for the diagnosis of CHF when BNP is tested on presentation to the emergency department [5–7]. Our data suggest that the potential complex interactions of intensive therapy (such as rapid changes in volume status, vasoactive medications, and positive pressure ventilation) may rapidly decay the diagnostic utility of BNP in the ICU. Diagnostic utility limited to the immediate presentation to the ICU may not be useful in many clinical settings.
In addition, despite a specificity of 90% for the diagnosis of ALI/ARDS at a cutoff of 250 pg/ml in the Rana study, those authors conclude that no level of BNP adequately ruled out a diagnosis of cardiogenic edema. Similarly, the authors suggested a BNP of more than 950 pg/ml as a threshold for diagnosing cardiogenic edema (positive likelihood 3.1 and negative likelihood of 0.7), leaving a large range of intermediate values (between 250 and 950 pg/ml) without diagnostic utility. We found 90% specificity for ALI/ARDS at a BNP of 157 or less; however, the corresponding sensitivity was only 30%, resulting in a positive likelihood ratio of 3.2 but a negative likelihood ratio of only 0.77. Higher levels of BNP showed improved sensitivity but at considerable cost to specificity. Even a BNP level of 1,000 pg/ml provided only modest (79%) sensitivity for diagnosing ALI/ARDS. Applying either of these upper (950 or 1,000 pg/ml) and lower (157 or 250 pg/ml) cutoffs to our cohort would result in 40 to 50% of test results falling in an intermediate and non-diagnostic range.
In our study, serial measurements of BNP did not correlate with day-to-day changes in invasive measures of filling pressures or net fluid balance. Recent clinical trials have shown improved clinical outcomes in patients with ALI/ARDS, with fluid management strategies targeting lower filling pressures or a negative fluid balance [23, 24]. Our data suggest that BNP measurements will not be useful for monitoring the effects of fluid management strategies in ICU patients.
Our study has several limitations. First, it is limited to a relatively small sample size at a single center. However, given the significant overlap in BNP levels between cohorts, it is not likely that a larger sample would significantly affect our results. We found an ROC curve with an AUC of 0.67 (95% confidence interval 0.52 to 0.82). Doubling our sample size to 104 patients, while maintaining the same ratio of ALI/ARDS to CHF patients, would probably have had little effect, because the 95% confidence interval of the AUC would only narrow to 0.57 to 0.77. Second, we present a correlation between BNP levels and invasive measures of filling pressures. In critically ill patients with the potential for increased pleural pressures, filling pressures may not be reliable surrogates for cardiac volumes. Finally, despite our best efforts to eliminate coexisting cases of ALI/ARDS and CHF, at least some degree of overlap is suggested by the less than 100% (50 of 54 patients) agreement on final classification by experienced intensivists. However, as the results of the recent ARDS Network study of fluid management in ALI/ARDS suggest, this dilemma is likely to be even more prevalent in clinical practice . In that trial, despite standard consensus inclusion and exclusion criteria, 30% of patients enrolled with ALI/ARDS had a PCWP of more than 18 mmHg at initial placement of a pulmonary artery catheter. More importantly, this study found a shorter duration of mechanical ventilation and ICU stay with a conservative fluid strategy, suggesting that some degree of hydrostatic edema is present in many cases of ALI/ARDS. These results suggest that a clear distinction between ALI/ARDS and cardiogenic edema is not likely with any diagnostic modality and may not be clinically relevant with regard to fluid management.
However, early recognition of ALI/ARDS remains important in improving clinician compliance with lung protective ventilation and in the diagnosis and treatment of underlying etiologies. Unfortunately, an increased use of BNP levels in the ICU is not likely to assist clinicians in this regard.
In our study, BNP testing within 48 hours of recognition of pulmonary edema and ICU admission did not reliably distinguish ALI/ARDS from cardiogenic pulmonary edema. This failure occurred despite efforts to exclude patients with coexisting conditions. Applying cutoff values at the low and high ends of the spectrum provided some utility in diagnosing ALI/ARDS and cardiogenic edema, respectively, but left many results in an intermediate and non-diagnostic range. Overlapping cases of ALI/ARDS and cardiac dysfunction are common in critically ill patients and will probably limit the clinical utility of BNP testing in this setting. In addition, serial sampling of BNP levels did not correlate with changes in invasive measures of filling pressure or net fluid balance, suggesting little role for use in monitoring effects of therapy.
BNP levels drawn within 48 hours of developing pulmonary edema did not reliably distinguish acute lung injury from cardiogenic pulmonary edema in critically ill patients despite the exclusion of patients with overlapping conditions.
BNP levels drawn simultaneously with invasive measures of filling pressures showed poor correlation with central venous and PCWP values.
Serial measurements of BNP drawn on up to three consecutive days showed poor correlation with changes in invasive measures of filling pressures and net 24-hour fluid status.
Despite increased use and ongoing need, BNP levels are not a reliable noninvasive surrogate for volume status in critically ill patients.
= acute lung injury
= acute respiratory distress syndrome
= area under curve
= B-type natriuretic peptide
= congestive heart failure
= intensive care unit
= left ventricular dysfunction
= pulmonary capillary wedge pressure
= right atrial pressure
= receiver operating characteristic.
We are indebted to Dr Allen Anderson for providing the BNP rapid fluorescence immunoassay.
- The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000, 342: 1301-1308. 10.1056/NEJM200005043421801View ArticleGoogle Scholar
- Rubenfeld GD, Cooper C, Carter G, Thompson BT, Hudson LD: Barriers to providing lung-protective ventilation to patients with acute lung injury. Crit Care Med 2004, 32: 1289-1293. 10.1097/01.CCM.0000127266.39560.96View ArticleGoogle Scholar
- Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R: The American–European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994, 149: 818-824.View ArticleGoogle Scholar
- Wheeler AP, Bernard GR, Thompson BT, Schoenfeld D, Wiedemann HP, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL: Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006, 354: 2213-2224. 10.1056/NEJMoa061895View ArticleGoogle Scholar
- Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA: Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002, 347: 161-167. 10.1056/NEJMoa020233View ArticleGoogle Scholar
- 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: 202-209. 10.1016/S0735-1097(01)01744-2View ArticleGoogle Scholar
- Mueller C, Scholer A, Laule-Kilian K, Martina B, Schindler C, Buser P, Pfisterer M, Perruchoud AP: Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004, 350: 647-654. 10.1056/NEJMoa031681View ArticleGoogle Scholar
- Jefic D, Lee JW, Savoy-Moore RT, Rosman HS: Utility of B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide in evaluation of respiratory failure in critically ill patients. Chest 2005, 128: 288-295. 10.1378/chest.128.1.288View ArticleGoogle Scholar
- Januzzi JL, Morss A, Tung R, Pino R, Fifer MA, Thompson BT, Lee-Lewandrowski E: Natriuretic peptide testing for the evaluation of critically ill patients with shock in the intensive care unit: a prospective cohort study. Crit Care 2006, 10: R37. 10.1186/cc4839PubMed CentralView ArticleGoogle Scholar
- Rudiger A, Gasser S, Fischler M, Hornemann T, von Eckardstein A, Maggiorini M: Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with severe sepsis, septic shock, and acute heart failure. Crit Care Med 2006, 34: 2140-2144. 10.1097/01.CCM.0000229144.97624.90View ArticleGoogle Scholar
- Tung RH, Garcia C, Morss AM, Pino RM, Fifer MA, Thompson BT, Lewandrowski K, Lee-Lewandrowski E, Januzzi JL: Utility of B-type natriuretic peptide for the evaluation of intensive care unit shock. Crit Care Med 2004, 32: 1643-1647. 10.1097/01.CCM.0000133694.28370.7FView ArticleGoogle Scholar
- Rana R, Vlahakis NE, Daniels CE, Jaffe AS, Klee GG, Hubmayr RD, Gajic O: B-type natriuretic peptide in the assessment of acute lung injury and cardiogenic pulmonary edema. Crit Care Med 2006, 34: 1941-1946. 10.1097/01.CCM.0000220492.15645.47View ArticleGoogle Scholar
- Wu AH, Smith A, Apple FS: Optimum blood collection intervals for B-type natriuretic peptide testing in patients with heart failure. Am J Cardiol 2004, 93: 1562-1563. 10.1016/j.amjcard.2004.02.072View ArticleGoogle Scholar
- Sudoh T, Maekawa K, Kojima M, Minamino N, Kangawa K, Matsuo H: Cloning and sequence analysis of cDNA encoding a precursor for human brain natriuretic peptide. Biochem Biophys Res Commun 1989, 159: 1427-1434. 10.1016/0006-291X(89)92269-9View ArticleGoogle Scholar
- Kojima M, Minamino N, Kangawa K, Matsuo H: Cloning and sequence analysis of cDNA encoding a precursor for rat brain natriuretic peptide. Biochem Biophys Res Commun 1989, 159: 1420-1426. 10.1016/0006-291X(89)92268-7View ArticleGoogle Scholar
- Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med 1985, 13: 818-829. 10.1097/00003246-198510000-00009View ArticleGoogle Scholar
- Murray JF, Matthay MA, Luce JM, Flick MR: An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988, 138: 720-723.View ArticleGoogle Scholar
- S Konstantinides, A Geibel, G Heusel, F Heinrich, W Kasper: Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002, 347: 1143-1150. 10.1056/NEJMoa021274View ArticleGoogle Scholar
- Charpentier J, Luyt CE, Fulla Y, Vinsonneau C, Cariou A, Grabar S, Dhainaut JF, Mira JP, Chiche JD: Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med 2004, 32: 660-665. 10.1097/01.CCM.0000114827.93410.D8View ArticleGoogle Scholar
- Rudiger A, Fischler M, Harpes P, Gasser S, Hornemann T, von Eckardstein A, Maggiorini M: In critically ill patients, B-type natriuretic peptide (BNP) and N-terminal pro-BNP levels correlate with C-reactive protein values and leukocyte counts. Int J Cardiol 2007.Google Scholar
- Vieillard-Baron A, Schmitt JM, Augarde R, Fellahi JL, Prin S, Page B, Beauchet A, Jardin F: Acute cor pulmonale in acute respiratory distress syndrome submitted to protective ventilation: incidence, clinical implications, and prognosis. Crit Care Med 2001, 29: 1551-1555. 10.1097/00003246-200108000-00009View ArticleGoogle Scholar
- Nagaya N, Nishikimi T, Okano Y, Uematsu M, Satoh T, Kyotani S, Kuribayashi S, Hamada S, Kakishita M, Nakanishi N, Takamiya M, Kunieda T, Matsuo H, Kangawa K: Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998, 31: 202-208. 10.1016/S0735-1097(97)00452-XView ArticleGoogle Scholar
- Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006, 354: 2564-2575. 10.1056/NEJMoa062200View ArticleGoogle Scholar
- Martin GS, Moss M, Wheeler AP, Mealer M, Morris JA, Bernard GR: A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med 2005, 33: 1681-1687. 10.1097/01.CCM.0000171539.47006.02View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.