Brain-type natriuretic peptide (BNP) and its prohormone (pro-BNP) are synthesised primarily in the myocardium in response to ventricular dysfunction and increasing ventricular wall tension. It promotes natriuresis, diuresis and vasodilation, and it is subsequently renally excreted.1 The concentrations of both BNP and its inactive aminoterminal cometabolite (amino-terminal pro-brain natriuretic peptide; NT-pro-BNP) in the blood are increased in patients with ventricular dysfunction and congestive heart failure.2,3 BNP and NT-pro-BNP are now well established as cardiac biomarkers, useful in diagnosing or excluding heart failure, as well as in managing and predicting mortality in patients with heart failure.4–6 In recent years, the clinical role of BNP and NT-pro-BNP in intensive care have been studied. The potential of BNP and NT-pro-BNP in detecting ventricular dysfunction and in discriminating between acute respiratory distress syndrome and cardiogenic pulmonary oedema has been studied.7–9 Furthermore, their ability to predict weaning failure and to serve as an alternative to invasive hemodynamic monitoring has been assessed.10–12 Other studies have focused on NT-pro-BNP as a marker for ICU outcome with conflicting results and its role as a predictor has not yet been fully established.13–17
The aim of this study was to further evaluate the incidence and prognostic role of an increased concentration of NT-pro-BNP in a general ICU population. Our hypothesis was that NT-pro-BNP can be used as a prognostic marker for death within 30 days of ICU discharge.
This study was approved by the Regional Research Ethics Committee of Linköping University, Linköping, Sweden (Chairperson Brita Swahn). The study was performed as a retrospective analysis of prospectively collected data. All clinical and laboratory data collected were part of routine registration of patients admitted to the ICU and the requirement for informed consent was waived.
Data was collected from the charts of 481 consecutive patients, aged 16 years or older, admitted to a mixed, noncardiothoracic, tertiary general ICU in a university hospital, from June 2009 to November 2010. Data on characteristics, admission details and severity of illness using the Simplified Acute Physiology Score 3 (SAPS 3) and the Sequential Organ Failure Assessment score (SOFA) were collected, in addition to data on clinical outcome. In all patients, plasma concentrations of NT-pro-BNP and serum concentrations of creatinine were analysed on admission as part of routine blood samples using an Elecsys 2010 (Roche Diagnostics, Mannheim, Germany).
The primary outcome was the incidence of elevated levels of NT-pro-BNP and its relation to all-cause mortality within 30 days after admission. Secondary outcome variables were ICU mortality and ICU length of stay.
The association between baseline characteristics and plasma concentrations of NT-pro-BNP was explored using unpaired Student's t-test for continuous variables, the χ2-test for dichotomous data and the Mann–Whitney U-test for nonparametric variables. Data on age, length of stay, severity of illness scores and laboratory data were not normally distributed, and are therefore expressed as medians and interquartile ranges (IQR).
To identify the NT-pro-BNP value that best predicted death within 30 days, a receiver–operating characteristic (ROC) curve was plotted. The area under the curve and 95% confidence intervals (CI) are presented. The best cutoff point was defined as the value providing the best sensitivity and specificity. A Kaplan–Meier analysis was performed to assess survival. According to the discriminatory NT-pro-BNP level, data were divided into two curves, which were then compared using a log-rank test. A univariate logistic regression analysis was used to identify clinical variables predicting death. Variables with a P value less than 0.05 were included in a stepwise logistic regression analysis to test the independence of the predictors, and results are presented as odds ratios (OR) and 95% CI. To analyse the correlation among SAPS 3, SOFA and NT-pro-BNP values on admission, Spearman nonparametric correlation coefficients were calculated. Furthermore, NT-pro-BNP values in the cohort were divided into quartiles and a logistic regression model was used to further evaluate its predictive value. A P value of 0.05 was considered significant. All analyses were performed using STATA v11.1 (Stata Corp LP, College Station, Texas, USA).
Four hundred and eighty-one patients were included in the analyses, and patient characteristics are shown in Table 1. In nonsurvivors, the median (IQR) NT-pro-BNP concentration was markedly elevated, as compared to survivors [2690 ng l−1 (440 to 8100) vs. 1040 ng l−1 (130 to 2800); P < 0.001].
A ROC curve analysis was used to identify the level of NT-pro-BNP that best predicted death in the ICU as well as within 30 days. An NT-pro-BNP concentration of 1380 ng l−1 or more had a sensitivity of 70% and a specificity of 58% for predicting ICU mortality, odds ratio 1.8. The area under the ROC curve was 0.66 (95% CI, 0.59 to 0.76). The same value, 1380 ng l−1, was also the best predictor of mortality within 30 days, with a sensitivity of 65% and a specificity of 62%, odds ratio 1.7. The area under the ROC curve was 0.68 (95% CI, 0.61 to 0.70).
Two hundred and fourteen patients presented with a NT-pro-BNP concentration of 1380 ng l−1 or more on admission. The characteristics of patients with NT-pro-BNP less than 1380 ng l−1 and 1380 ng l−1 or more, respectively, are presented in Table 2. Patients with NT-pro-BNP concentration of 1380 ng l−1 or more were older and had higher severity of illness scores than patients with NT-pro-BNP below this value. In patients with NT-pro-BNP concentration of 1380 ng l−1 or more, the reason for ICU admission was more often severe sepsis or septic shock, and they had a higher incidence of renal failure. However, the requirement for mechanical ventilation did not differ between patients with NT-pro-BNP concentrations of 1380 ng l−1 or more and those below this value.
Figure 1 shows a Kaplan–Meier survival curve for 30-day mortality. As shown, a NT-pro-BNP concentration above 1380 ng l−1 is correlated with an increased risk of death within 30 days of admission to ICU, P = 0.005. An elevated NT-pro-BNP concentration was associated with a higher risk of death within 30 days after ICU admission in a univariate logistic analysis. When adjusting for confounding factors (age, sex, severe sepsis or septic shock, serum concentrations of creatinine, mechanical ventilation and ICU length of stay) in a stepwise logistic regression analysis, a NT-pro-BNP concentration of 1380 ng l−1 or more was found to be an independent predictor of mortality within 30 days (OR 2.6; 95% CI, 1.5 to 4.4). The correlation between SAPS 3 and SOFA on admission in the cohort using Spearman's ρ was 0.5944. The correlation of NT-pro-BNP to SOFA was Spearman's ρ 0.5129, and 0.5552 to SAPS 3.
To further evaluate the risk associated with an elevated NT-pro-BNP concentration, the cohort was divided into quartiles. As shown in Table 3, with increasing levels of NT-pro-BNP, patients were older and had higher severity of illness scores. They were more often septic and they presented more frequently with renal insufficiency, but there was no difference with regards to the need for mechanical ventilation in the different quartiles. Furthermore, ICU mortality as well as mortality within 30 days increased with higher NT-pro-BNP values (Table 3). Table 4 shows ORs for death with regards to ICU and 30-day mortality in the quartiles.
In this prospective observational study on patients admitted to a mixed tertiary ICU, we found that NT-pro-BNP concentration was an independent predictor of ICU mortality, as well as of mortality within 30 days.
There has been increasing interest in the use of NT-pro-BNP and BNP as prognostic markers in critical care settings in recent years. Previous studies on NT-pro-BNP and intensive care outcome have shown that elevated levels of NT-pro-BNP independently predict mortality in the ICU and within 30 days.14,15,17,18 However, earlier studies have focused on specific groups of patients such as postoperative patients, those with left ventricular dysfunction, septic patients or patients in shock.4,12,18,19 One recently published study focused on NT-pro-BNP in a large group of patients with acute respiratory insufficiency requiring either invasive or noninvasive mechanical lung ventilation. An increased NT-pro-BNP concentration was associated with an increased risk of death, but the authors concluded that it did not provide additional value to other clinical data.20 Indeed, it has been suggested that mechanical ventilation itself may influence NT-pro-BNP levels.14,17 In contrast, we found that the need for mechanical ventilation did not differ between groups of patients with higher or lower NT-pro-BNP values.
This is the first study of this size in a mixed ICU setting, and could therefore be considered to represent a typical ICU patient population. One might argue that an elevated NT-pro-BNP concentration in such a varied patient population is not sufficiently specific to be useful. However, although the pathophysiology of elevated natriuretic peptides in an ICU setting is still to some extent unknown, we do know that NT-pro-BNP and BNP are released in response to wall stress in ventricular myocytes.4 This might result from a wide variety of clinical conditions in the ICU, including ventricular dysfunction caused by sepsis, acute respiratory distress, acute lung injury, pulmonary embolism and fluid resuscitation itself, and regardless, an elevated NT-pro-BNP concentration is related to an increase in ICU mortality.21–24
We found an NT-pro-BNP value of 1380 ng l−1 to have the best sensitivity and specificity for predicting ICU mortality, as well as 30-day mortality. This level correlates with that reported in earlier studies, as well as with the threshold level used for diagnosing heart failure (>900 ng l−1 in patients 50 to 75 years old, and >1800 ng l−1 in patients >75 years).17 The accuracy of the receiver operating curve determining this cutoff value was a moderate 66% for ICU mortality and 68% for 30-day mortality, respectively. However, these values are in the same range as in other studies.14 Even so, a NT-pro-BNP concentration above this value was a strong predictor of mortality, independent of age, sex and sepsis. Interestingly, its predictive ability was also independent of ICU length of stay. This is despite the fact that the study cohort contains patients with a very short stay in the ICU, including patients receiving postoperative care after major surgery and patients admitted for short-term observation after intoxication or trauma.
Another important consideration when interpreting NT-pro-BNP in critically ill patients is the possible impact of renal insufficiency, as NT-pro-BNP is renally excreted.1 In this study, patients with an elevated NT-pro-BNP concentration had a higher incidence of renal failure, expressed as serum creatinine more than 170 μmol l−1, than patients with NT-pro-BNP concentrations below the diagnostic threshold, and the presence of renal failure may have influenced the NT-pro-BNP levels measured. However, our aim was to study a nonselected group of ICU patients and patients with elevated creatinine levels were not excluded from the analysis. Still, the predictive value of NT-pro-BNP was independent of creatinine levels, as well as of clinical factors stated above.
The ability of NT-pro-BNP to predict mortality has previously been shown to be comparable with that of SAPS II and the Acute Physiology and Chronic Health Evaluation II scores.14,15,18 We found a similar pattern when comparing the prognostic value of NT-pro-BNP with that of the now more widely used SAPS 3, as well as to SOFA. We believe that the natriuretic peptides could be used in predicting outcome as a complement to conventional, more complex intensive care scoring models, such as SAPS 3.
Previous studies have shown a pattern of increasing mortality with increasing levels of NT-pro-BNP.14,15,18 We have further evaluated the prognostic role of NT-pro-BNP by clinical data and outcome rates according to quartiles of NT-pro-BNP elevation. This shows a pattern of older, more severely ill and more often septic patients with a longer ICU stay, with increasing NT-pro-BNP levels, in line with the results discussed above, as well as a higher ICU mortality and 30-day mortality. Interestingly, just as with groups of patients above and below the discriminatory threshold, the need for mechanical lung ventilation, even on admission, did not differ between quartiles. This could further argue against previous studies suggesting an influence by mechanical ventilation on the level of NT-pro-BNP. It could instead encourage the use of NT-pro-BNP in the large group of ICU patients requiring mechanical ventilation.
This is the first study assessing the predictive ability of NT-pro-BNP in a large and unselected general ICU population. It expands previous knowledge on the independence of NT-pro-BNP as a predictor of ICU outcome, and suggests that analysing NT-pro-BNP is of great value in ICU patients, irrespective of reason for admission. Furthermore, it adds to previous data on the pattern of critical illness as an effect of the degree of NT-pro-BNP elevation. Thus, this study provides additional value to NT-pro-BNP as an aid in clinical decision-making on treatment in intensive care patients.
There are limitations to our study. NT-pro-BNP was analysed on admission only. Our hospital is a tertiary unit, and some patients are transferred here from other hospitals. Hence, admission to our ICU could be late in an individual patient's clinical course. Repeated measurements of NT-pro-BNP might have shown a better correlation between the dynamics of NT-pro-BNP and that of critical illness. Also, performing echocardiography on the patients could have provided additional knowledge of the reason for NT-pro-BNP elevation. Furthermore, as NT-pro-BNP is part of our routine laboratory analyses, clinicians were not blinded to the results, and this could be argued to have influenced clinical decisions. Finally, the inclusion of all patients with no discrimination between groups may be a weakness of our study. However, our objective was not to explore NT-pro-BNP as a diagnostic tool, but to analyse its predictive ability.
In conclusion, we found that NT-pro-BNP concentration is markedly elevated in a mixed critically ill patient population, that it increases with severity of illness, and that it is an independent predictor of both ICU and 30-day mortality. However, in view of current data, NT-pro-BNP should be used only as an addition to other clinical and laboratory data for clinical decision-making in critically ill patients.
No external funding and no conflicts of interest declared.
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Keywords:© 2012 European Society of Anaesthesiology
brain natriuretic peptide; intensive care; survival rate