UNDERSTANDING THE ROLE OF NT-proBNP IN SEPTIC SHOCK: BEYOND CARDIAC DYSFUNCTION
Year: 2024
Type: article
Study design: Observational Study
Abstract: We want to highlight an intriguing relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and markers of capillary leakage observed incidentally in patients with septic shock. NT-proBNP is a well-established biomarker indicating the severity of congestive heart failure, closely associated with cardiomyocyte stress and adverse outcomes in ischemic heart disease patients.(1) In sepsis, elevated NT-proBNP levels have been correlated with worse outcomes,(2) and it has shown superior predictive value for 90-day mortality compared to the SOFA score.(3) However, the precise nature of its relationship to cardiac dysfunction, direct cardiac injury, or volume overload remains unclear. Notably, NT-proBNP elevation in septic shock appears independent of ventricular dysfunction and the patient’s fluid status.(4) Our brief report aims to present the as-yet unexplored connection between NT-proBNP and capillary leakage in septic shock, potentially explaining its elevation in inflammatory states. We conducted a retrospective analysis on patients admitted to the intensive care unit (ICU) between January and October 2023. We identified subjects with septic shock who had NT-proBNP measured upon ICU admission. Subsequently, we assessed the correlation between NT-proBNP and admission values of highly sensitive cardiac troponin T (hs-TnT), serum creatinine, albumin, interleukin-6 (IL-6), and norepinephrine dose. Capillary leakage was primarily estimated using serum albumin levels, as hypoalbuminemia is an early finding in bacteremia due to an increased trans-capillary escape rate without a corresponding decrease in hematocrit.(5) Additionally, we calculated the modified capillary leak index (CLIm) as the base-10 logarithm of IL-6 to serum albumin ratio. The capillary leak index (CLI), originally defined as the C-reactive protein (CRP) to serum albumin ratio, was validated by Cordemans et al. to quantify the level of capillary leakage.(6) We decided to adapt the CLI due to the positive correlation between IL-6 and CRP; nonetheless, IL-6 demonstrates an earlier increase and, thus, superior diagnostic accuracy for identifying septic shock compared to CRP.(7) To account for the inflammatory-induced decrease in albumin synthesis during early septic shock, we evaluated the correlation between IL-6 and serum albumin. Correlations were estimated using the Spearman coefficient (r), and data are presented as medians with their corresponding minimum and maximum values. During the study period, 50 patients were admitted for septic shock, of which only 15 had all monitored biomarkers evaluated upon ICU admission. The median age was 74 years (range: 21–79). All patients were mechanically ventilated and required norepinephrine support at a median dose of 0.38 μg/kg/min (range: 0.06–0.85). Ten patients received concomitant vasopressin, and eight underwent echocardiography upon admission, revealing only one with a left ventricular ejection fraction below 45%. Median biomarker levels observed were as follows: NT-proBNP 5,105 ng/L (range: 745–23,721), CLIm 0.14 (range: 0.08–0.22), hs-TnT 88.5 ng/L (range: 15–2,097), IL-6 3,600 ng/L (range: 1,200–52,000), serum albumin 28 g/L (range: 18–39), and serum creatinine 185 μmol/L (range: 63–500). We found a strong positive correlation between NT-proBNP and CLIm (Fig. 1A; r = 0.7, P = 0.005), as well as between NT-proBNP and IL-6 (Fig. 1B; r = 0.62, P = 0.02). A negative correlation was observed between NT-proBNP and serum albumin (Fig. 1C; r = −0.54, P = 0.04). Conversely, there were no significant correlations between NT-proBNP and hs-TnT (Fig. 1D; r = 0.28, P = 0.31), serum creatinine (not shown; r = 0.19, P = 0.5), or norepinephrine dose (not shown; r = −0.12, P = 0.67). Additionally, no correlation was found between IL-6 and serum albumin (not shown; r = −0.15, P = 0.59).Fig. 1: Correlation between NT-proBNP and modified capillary leak index (A), IL-6 (B), serum albumin (C), and hs-TnT (D). These biomarkers were taken upon the admission of 15 patients diagnosed with septic shock. Median values, along with the minimum and maximum values for each parameter, are detailed within the main text. For biomarkers exhibiting a wide range of values (NT-proBNP, IL-6, and hs-TnT), a base-10 logarithmic scale was employed to facilitate visualization. The depicted solid line signifies the simple linear regression line calculated using the Theil-Sen estimator. The Spearman coefficient (r) is presented to quantify the strength of the correlation alongside the corresponding P value to assess statistical significance. hs-TnT, highly sensitive cardiac troponin T; NT-proBNP, N-terminal pro-B-type natriuretic peptide.Our preliminary findings suggest that the increase in NT-proBNP observed in septic shock patients is unlikely due to cardiomyocyte damage or catecholamine-induced stress. Furthermore, there seems to be no significant link between elevated NT-proBNP and altered renal function. Instead, the positive correlation with IL-6 supports the notion that NT-proBNP elevation is part of the acute inflammatory response. The strong association observed between NT-proBNP, serum albumin, and CLIm indicates that NT-proBNP may serve as a marker reflecting the extent of capillary leakage induced by inflammation. Interestingly, NT-proBNP may not only serve as a marker of capillary leakage but also contribute to increased capillary leakage by promoting glycocalyx shedding, possibly through the activation of metalloproteases.(8) Given that glycocalyx degradation is well-documented in septic patients, the focus on managing septic shock through glycocalyx-preserving strategies remains a topic of ongoing debate.(9) The relationship between inflammation and elevated circulating levels of natriuretic peptides has been already documented.(10) Cytokines, particularly IL-6, are known to stimulate the synthesis of natriuretic peptides in the heart, likely through cytokine-responsive elements on the NPPB gene promoter.(11,12) However, the precise biological role of elevated NT-proBNP in the inflammatory process remains unclear. As discussed earlier, NT-proBNP may induce glycocalyx shedding, potentially facilitating the transendothelial migration of leukocytes into injured tissues, thereby further amplifying the inflammatory response.(13) The utilization of serum albumin for assessing capillary leakage is substantiated by its early measurement shortly after septic shock onset. This timing implies that the observed hypoalbuminemia likely predominantly stems from an increased trans-capillary escape rate, as documented in the literature.(5,14) Furthermore, the absence of correlation between IL-6 and serum albumin suggests that decreased albumin synthesis induced by inflammation may not be the primary contributing factor. It would be, however, expected that hypoalbuminemia correlates with IL-6 levels, as more severe inflammation typically results in greater capillary leakage.(15) Mediation analysis can help clarify this relationship by assessing whether, and to what extent, the association between IL-6 and serum albumin is mediated by NT-proBNP. Our analysis, using logarithmically transformed IL-6 values, revealed a significant Average Causal Mediation Effect (estimate: −2.409, P = 0.046), suggesting that IL-6 exerts a significant indirect effect on serum albumin via NT-proBNP. These preliminary findings indicate that as IL-6 increase, it provokes NT-proBNP elevation, which in turn contributes to decreased serum albumin. Our pilot study, with a limited sample size, is constrained by the absence of a relationship between NT-proBNP and markers of glycocalyx damage, which have not yet been incorporated into everyday clinical examinations. The low number of enrolled patients can be attributed to NT-proBNP not being routinely assessed in laboratory examinations upon admission of patients with septic shock. Finally, only half of the patients underwent echocardiography, which limits our ability to definitively rule out ventricular dysfunction as a contributor to elevated NT-proBNP. However, a previous study has shown that even in septic patients with no signs of systolic dysfunction on echocardiography, natriuretic peptide levels can still be elevated.(16) In conclusion, NT-proBNP in septic shock appears to extend beyond its role as a marker of cardiac dysfunction, potentially reflecting the acute inflammatory response to infection and showing promise as an indicator of capillary leakage. Further exploration into the exact relationship between NT-proBNP levels and the degree of glycocalyx damage is imperative for elucidating this association.
Source: Shock
Authors: Roman Kula, Marcin Osuchowski, Roman Kula
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4403767871