New insights into the mechanisms involved in B-type natriuretic peptide elevation and its prognostic value in septic patients

B-type natriuretic peptide (BNP) is a cardiac hormone with diuretic, natriuretic and vasorelaxing properties. It is considered to be produced by ventricular myocardium in response to increased wall stretch and plays a fundamental role in regulating cardiac filling pressure and intravascular volume homeostasis [1‐3]. Therefore, BNP is used widely in cardiology as a valuable biomarker of left ventricular (LV) dysfunction and increased LV filling pressure [2, 4‐6]. BNP levels may remain high despite appropriate therapy in heart failure, however, suggesting that stimuli other than LV pressure and/or volume overload may be implicated in the release of the peptide [7].

Plasma BNP concentrations may also be considerably high in patients with critical sepsis (henceforth, the term critical sepsis is used to include both severe sepsis and septic shock) [1, 8]. In such patients, BNP has been proposed as a valuable screening tool to detect underlying cardiac dysfunction (otherwise known as septic cardiomyopathy) [9‐11]. Several heterogeneous conditions may also account for increased BNP levels, such as the intensity of inflammation per se, vasopressors used, renal failure and right ventricular (RV) overload [1, 8, 12‐19]. Therefore, the primary conditions predisposing patients to BNP elevation in sepsis, as well as the associations between them, are largely undetermined. In addition, the diagnostic performance of BNP in predicting sepsis outcomes remains questionable [9‐11, 19‐21].

In this observational study, we sought potential independent determinants of BNP elevation in critical sepsis. We prospectively evaluated the influence of several clinical parameters, which have previously been associated with BNP rise [8‐19], on 5-day longitudinal BNP measurements in critical sepsis patients. These predefined parameters included (1) LV and RV systolic function; (2) LV and RV filling pressures and pulmonary artery catheter (PAC)–derived hemodynamic parameters; (3) sepsis severity classification systems, which reflect the intensity of systemic inflammation; (4) renal failure; (5) acute lung injury and acute respiratory distress syndrome; and (5) iatrogenic interventions (fluid and vasopressor infusion and ventilator settings). In order to provide further insight into the influence of noradrenaline infusion on BNP rise in critical sepsis, we also studied BNP levels in patients with hemorrhagic shock requiring noradrenaline support and PAC monitoring. Finally, we investigated the diagnostic role of BNP in predicting mortality in critical sepsis patients.

In this single-center observational study, we prospectively examined critically ill patients with severe sepsis and septic shock admitted to our general ICU during a 3-year period from February 2009 to January 2012. The inclusion criteria were (1) requirement of support with mechanical ventilation and (2) need for hemodynamic monitoring by using a PAC (with both criteria met for at least 3 days). Exclusion criteria were (1) younger than 18 years of age; (2) pregnancy; (3) chronic heart disease (coronary artery disease, cardiac failure, severe valvulopathy and/or cardiomyopathy); (4) chronic renal failure; (5) known pulmonary hypertension; (6) diseases of the central nervous system (CNS; for example, meningitis, brain abscess, cerebral hemorrhage), in which BNP levels are difficult to interpret [18]; (7) poor echocardiographic scan quality; and (8) infusion of inotropic agents (dopamine, dobutamine or levosimendan). Patients receiving noradrenaline were included in the study.

Preliminary data in three ICU patients with acute blood loss requiring noradrenaline infusion showed that BNP concentrations in hemorrhagic shock are extremely lower than in septic shock patients. Noradrenaline infusion is considered a potential stimulus for BNP increase [15]; however, its influence on BNP rise in critical sepsis is undefined. Thus, in order to provide further insight into the mechanisms involved in BNP production in critical sepsis, we decided to study BNP kinetics prospectively in a randomization arm of patients with hemorrhagic shock.

Patients with critical sepsis were managed according to the standard protocol of care for sepsis [22], including antibiotics, vasopressors, respiratory support and surgical intervention if indicated. Clinical management decisions were made by the attending physicians, including the intention to place a PAC for diagnosis or monitoring as part of standard care. All cases were discussed daily in a multidisciplinary meeting. Deaths that occurred within 28 days after ICU admission were recorded (that is, 28-day mortality). Patients were considered “survivors” if they survived for at least 28 days after admission.

The study protocol was approved by the Ethical and Educational Committee of the University Hospital of Larissa and conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Patients’ next of kin provided informed consent for all participants.

Forty-two patients with severe sepsis (N = 12) and septic shock (N = 30) fulfilled the eligibility criteria and were enrolled in the study. Eleven patients with hemorrhagic shock were also examined. Differences between groups according to their baseline clinical characteristics, admitting etiology and outcome are given in Table 1. Additional file 1 shows the clinical characteristics of our 42 patients in more detail.

PAC-derived hemodynamic measurements on day 1, 3-day recordings of PCWP and CVP and the incidence of LV and RV systolic dysfunction at baseline are listed in Table 2 (for further details see Additional file 1, “The incidence of LV and RV septic cardiomyopathy” section).

In the present study, we found BNP concentrations to be considerably elevated in septic shock patients compared with severe sepsis patients on every single day of assessment (P ≤ 0.002). This finding differs from the findings of McLean et al. [21], who reported no escalation of BNP levels from severe sepsis to septic shock, but it is consistent with the findings in the studies of Pirracchio et al. [16] and Ueda et al. [30]. As sepsis syndrome evolves and the patient’s condition continues to deteriorate, several mechanisms may be involved in BNP elevation, such as proinflammatory cytokine oversecretion [8, 12‐14], ensuing systolic and diastolic biventricular dysfunction [9, 10, 31], altered BNP clearance [16], renal failure [32] and sepsis-associated acute lung injury or acute respiratory distress syndrome [18]. In addition, several medical interventions employed with the aim of treating sepsis [22] may trigger BNP release, such as volume overresuscitation [17, 19] and high PEEP levels (both of which result in RV overload [33]), and catecholamine infusion [15].

In our series, the severity of sepsis (as indicated by increased APACHE II and maximum SOFA scores) and high noradrenaline levels on day 1 were independent determinants of serial BNP values. In addition, increased right-side filling pressures (CVP and CVP/PCWP ratio [25]) were independently associated with early BNP elevation in the subset of septic shock patients. Sepsis-induced LV and RV systolic dysfunction, although significantly associated with serial BNP measurements, were not independent predictors of BNP elevation. In contrast to previous data [32], demonstrating a correlation between BNP and PCWP in critically ill non-cardiac patients with preserved renal function, but in line with other previous reports [8, 11, 34, 35], we did not detect any relationship between serial PCWP measurements and the corresponding BNP values.

Our study provides evidence that it is the severity of critical illness rather than cardiac dysfunction that accounts for BNP release in the setting of critical sepsis (Table 3 and Additional file 4). In addition, the results of our study suggest that, in patients with septic shock, RV overload may play a pivotal role in early BNP rise and therefore should be carefully evaluated (Additional file 4). Researchers in previous studies have reported that BNP can be increased [8, 12, 14, 16] and cardiac contractility may be depressed [36] secondarily to the activation of several inflammatory mediators. On this ground, both septic cardiomyopathy and high BNP levels may be epiphenomena in severe sepsis patients. Unfortunately, we did not assess specific inflammatory markers [37] in our study.

Catecholamine oversecretion in critical sepsis patients may adversely influence cardiac function, coagulation (hypercoagulability and thrombus formation), immune system (immunomodulation and stimulation of bacterial growth) and metabolism (increase in cellular energy expenditure, hyperglycemia and impaired glucose tolerance, muscle catabolism, increased lipolysis and hyperlactatemia). Noradrenaline infusion may further impair organ function and cardiovascular homeostasis [38]. In an effort to better comprehend the impact of noradrenaline infusion on BNP production in septic shock patients, we assessed BNP concentrations in 11 patients with hemorrhagic shock. The peak noradrenaline dose was similar between the two types of shock (Table 1); however, BNP levels were extremely higher (approximately 20-fold greater) in septic shock patients than in hemorrhagic shock patients (Table 2 and Figure 1). Our findings suggest that it is neither noradrenaline infusion per se, as previously suggested [15], nor the severity of circulatory collapse, but rather the inflammatory nature of shock that primarily accounts for BNP elevation in critical sepsis patients [8, 12‐14]. Furthermore, in our critically septic patients, the level of vasopressor support was independently associated with mortality in the Cox proportional hazards analysis of survival (Table 4). Therefore, we hypothesize that peak noradrenaline dose on day 1 should be considered as another marker of the intensity of critical sepsis (along with the APACHE II and SOFA clinical grading systems, which were also independent determinants for BNP rise in this study) rather than an index of circulatory failure or an independent upregulating factor in BNP rise.

Ueda and co-workers [30], in a study in which they examined BNP trends in severe sepsis and septic shock patients, found that the BNP levels peaked on day 2 and decreased gradually afterward. Our data are in line with these findings; yet, we report greater BNP values on each study day. In the present study, instead of repeated measures of ANOVA [30], we used linear mixed model analysis to evaluate 5-day BNP kinetics, as the former has been criticized for producing biased results due to missing data (deceased patients) during the study period [39]. We found that BNP kinetics differed significantly in the two subgroups of critical sepsis patients, as the BNP concentrations demonstrated significantly steeper declines in septic shock patients than in severe sepsis patients (Figure 1). These findings may suggest a relatively steady state of BNP kinetics over time in severe sepsis patients, whereas the onset of septic shock is probably characterized by bursts of BNP secretion.

It has been reported previously that plasma BNP concentration on day 2 [10, 28, 30], on day 3 [9, 10] and even on day 5 [9] predicts mortality in septic shock patients. In contrast to these results, McLean et al. [21] and Rudiger et al. [34] failed to demonstrate any predictive utility of BNP concentration. In a recent meta-analysis [40], Wang et al. suggested that elevated BNP during the initial 5 days from the onset of critical sepsis may be a powerful predictor of mortality in septic patients; however, an ideal cutoff BNP value was not determined. Our data provide evidence that daily BNP levels are of limited diagnostic value in predicting 28-day mortality. In critical sepsis patients, early BNP elevation >800 pg/ml (day 1) and >840 pg/ml (day 2) may predict mortality and should be assessed. In the subgroup of septic shock patients, however, BNP level showed no prognostic value in ROC analysis (Additional file 7). Instead, 5-day BNP kinetics demonstrated a significant decline in survivors compared to nonsurvivors in both critical sepsis and septic shock patients (Figure 2). A plausible explanation for this finding is that isolated BNP values are likely to provide “instant images” of the severity of the disease and can be affected by several factors in critical illness. However, persistent elevation of BNP over time may imply intractable critical illness, despite appropriate therapeutic interventions, and, in this respect, it may be of great prognostic value.

In line with the discussion above, we show that the daily BNP percentage changes (relative to baseline values) corresponded well with the evolution of organ dysfunction assessed by SOFA score percentage alterations from baseline (Additional file 3). Notably, the 5-day BNP trends in our septic patients (Figure 2) are comparable to the previously reported APACHE scores in survivors and nonsurvivors [36]. These findings may suggest that the intensity of critical illness is probably the common denominator of BNP rise and decrease in critical sepsis patients. Furthermore, our findings provide evidence that an inability to reduce BNP levels below the critical threshold of 500 pg/ml may indicate poor outcomes in septic shock patients. Accordingly, prolonged BNP elevation should be assessed carefully in critical sepsis patients because it may imply an untreated underlying pathology, despite evidence of clinical improvement.

In the present study, we found that a BNP/CVP ratio >126 pg/ml/mmHg, measured on day 2, demonstrated potential prognostic significance in septic shock patients. CVP monitoring is the cornerstone for fluid resuscitation in septic shock patients [22]; thus the BNP/CVP ratio is easy to calculate. The prognostic importance of the BNP/CVP ratio is that it may provide prognostic information early in the course of septic shock. Although the greater the CVP, the higher the BNP values at baseline (Additional file 4), we found that disproportionately elevated BNP in relation to CVP after initial fluid resuscitation might predict increased mortality. Our findings may suggest that disastrous sepsis, except for increased BNP levels, is also associated with vascular underfilling, despite appropriate volume overexpansion [22], possibly due to extreme systemic vasoplegia and continuing fluid extravasation. It is intriguing to speculate that CVP-guided fluid resuscitation [22] might have been inadequate in some of our nonsurvivors; however, whether the BNP/CVP ratio may be of value in making decisions related to volume expansion by adding to established clinical data [22] should be elucidated in future studies.

In our septic patients, we found a greater incidence of RV than LV systolic dysfunction (Table 2). In addition, depressed RVEF, but not LVEF, showed an independent association with mortality (Table 4). However, RVEF and LVEF were strongly interrelated (Additional file 1), and both were significantly associated with serial BNP measurements (Table 3). Although mechanical ventilation and/or hypoxemia may increase PVRI, thus unmasking RV dysfunction, systemic vasoplegia may conceal impaired LV contractility, resulting in an artificially elevated LVEF [41]. We hypothesized that myocardial depression in sepsis is global rather than right-sided; however, our findings suggest that a PAC-derived RVEF may reflect septic cardiomyopathy better than echocardiography and may have greater diagnostic and prognostic value in mechanically ventilated septic patients.

We acknowledge that there are some points that have to be considered in the interpretation of our results. First, 28-day mortality was 56.7% in septic shock patients and 47.6% in critical sepsis patients. These mortality rates may be comparable to those reported by previous researchers who studied similar ICU patient populations [42, 43], but they are higher than currently expected in the general population of critical sepsis patients [44]. Despite the fact that direct comparisons with historical studies are difficult because of differences in study populations and designs, these differences are likely to be due to the severity of critical illness and potential comorbidities. Second, LVEF values may have been affected by changes in cardiac loading conditions. Certainly, less load-dependent echocardiographic indices of LV contractility, such as tissue Doppler imaging–derived mitral annular velocities [45], might have provided further insight into the role of septic cardiomyopathy in BNP elevation. However, PAC-derived LVSWI, which is considered a less load-dependent index of LV contractility [46], also failed to demonstrate an independent association with BNP, probably suggesting that septic cardiomyopathy is not the major determinant of BNP rise. Third, dynamic indices of volume responsiveness (pulse pressure variation and stroke volume variation) might have identified responders to volume expansion more precisely than cardiac filling pressures (CVP and PCWP) [47]. However, CVP-guided fluid resuscitation was the existing clinical practice at the time our study was conducted [22]. Fourth, troponin measurements were not performed systematically in our patients, which is a potential limitation of our study. Newer, highly sensitive assays that enable clinicians to identify previously undetected pathological troponin levels [48] may provide more information on the role of myocardial damage in BNP elevation in septic patients.

Our study has several strengths and originality. We evaluated cardiac function and hemodynamics as potential determinants of BNP secretion by using both right heart catheterization and echocardiography. Moreover, we used a PAC equipped with a rapid response thermistor for the assessment of RV systolic function, as echocardiographic estimation of RV systolic function in mechanically ventilated ICU patients is considered problematic in terms of feasibility and reproducibility [49]. In addition, by comparing septic patients with hemorrhagic shock patients, we provide evidence that noradrenalin dose may not be a stimulus of BNP secretion per se.

Our data clearly show that the severity of illness, rather than sepsis-induced myocardial depression, is the main determinant of BNP increase in mechanically ventilated patients with critical sepsis. Increased LV filling pressures and volume overexpansion during the acute phase of critical sepsis were not associated with BNP elevation in our series. Our findings also suggest that increased baseline BNP values >800 pg/ml and BNP/CVP ratio >126 pg/mmHg¹/ml on day 2 may be early predictors of adverse outcomes. In addition, prolonged BNP elevation and inability to reduce BNP below the critical threshold of 500 pg/ml may also imply increased mortality. In this respect, our study results suggest that both baseline BNP values and BNP trends should be carefully assessed in the acute phase of critical sepsis and possibly considered in the management of the disease.