Clinical usefulness of NT-proBNP as a prognostic factor for septic shock patients presenting to the emergency department

Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level is primarily used as a biomarker for left ventricular (LV) dysfunction. It is influenced by various conditions, such as myocardial strain and situations affecting the clearance of NT-proBNP, including sepsis and shock. In this study, we investigated the appropriateness of NT-proBNP as a prognostic factor for septic shock. Patients with septic shock who visited the emergency department of the Ewha Womans’ University Mokdong Hospital between January 1, 2018, and December 31, 2020, were classified into the survival group (those who survived in the hospital and were discharged) and the death group (those who died in the hospital). The effectiveness of NT-proBNP, lactate, and blood urea nitrogen as predictive factors of in-hospital mortality was evaluated using the area under the receiver operating characteristic (AUROC) curve. The AUROC curve was 0.678 and 0.648 for lactate and NT-proBNP, respectively, with lactate showing the highest value. However, there was no significant difference between lactate and NT-proBNP levels in the comparison of their AUROC curve (p = 0.6278). NT-proBNP could be a useful predictor of in-hospital mortality in patients with septic shock who present to the emergency department.


Statistical analysis
The Mann-Whitney U test was used for the analysis of continuous variables, while the chi-squared test or Fisher's exact test was used for categorical variables, depending on appropriateness.Quantitative data are presented as medians with interquartile ranges, whereas categorical data are expressed as numbers and percentages.Statistical significance was set at a two-tailed p-value < 0.05.Analysis was conducted using the Statistical Package for the Social Science (SPSS) version 26.
To assess predictive accuracy, receiver operating characteristic (ROC) curve analysis was performed for WBC, neutrophil, BUN, creatinine, CRP, lactate, procalcitonin, NT-proBNP, and arterial pH.MedCalc statistical software version 19.4.1 was employed for the ROC curve analysis.
The method of DeLong et al. 23 was used to calculate the standard error of the area under the curve (AUC) and the difference between the two AUCs.The predictive accuracy for in-hospital mortality was compared among early blood test measurements using area under the ROC curve (AUROC) and 95% confidence interval (CI).
The optimal cutoff points for each blood test were determined using the Youden Index of ROC curves.Sensitivity, specificity, positive likelihood ratio (+ LR), and negative likelihood ratio (-LR).CI was used to estimate the prognostic accuracy of each criterion for the proposed cutoff points.

Ethics statement
This study was approved by the Institutional Review Board (IRB) of the Ewha Womans University Mokdong Hospital (IRB No. 2023-04-008).All methods were carried out in accordance with relevant guidelines and regulations.The need for informed consent was waived by the IRB of Ewha Womans University Mokdong Hospital (IRB No. 2023-04-008) because of the retrospective nature of the study, and patient information was anonymized before analysis to ensure confidentiality.

Patient baseline
The participants were 418 patients with septic shock (Fig. 1).During the study period, 307 patients survived and were discharged (survival group), and 111 patients died (death group) (Table 1).The median age of the survival group was 76 years old (IQR: 64.00-82.00),and that of the death group was 79 years old (IQR: 70.00-84.00,p < 0.05).The study sample comprised 241 males (57.7%) and 177 females (42.3%).In both groups, most patients with septic shock were hypertensive (143 and 50 patients, respectively), and the only significant difference between the groups was the incidence of stroke (p < 0.05).The most common symptom reported in both groups was dyspnea (survival vs. death; n = 85, 27.7% vs. n = 42, 37.8%).The second most frequently reported symptom differed between the two groups: it was fever in the survival group (n = 77, 25.1%) but altered mental status in the death group (n = 28, 25.2%, p < 0.05).At the time of arrival in the ED, the level of consciousness was predominantly alert in the survival group (n = 160, 52.1%), whereas the death group had a higher proportion of patients with pain-responsive consciousness (n = 43, 38.7%; p < 0.05).

Comparison of laboratory test and management
Among the various blood tests performed (Table 2), only BUN, creatinine, CRP, procalcitonin, NT-proBNP, lactate, and arterial pH showed significant differences between the groups (p < 0.05).
Patients who received mechanical ventilation had a rate of 26.1% (n = 80) in the survival group compared with 60.4% (n = 67, p < 0.05) in the death group.Among the patients who received continuous renal replacement therapy, the survival group had a rate of 6.5% (n = 20), whereas the death group had a rate of 21.6% (n = 24, p < 0.05).The blood culture test did not detect any bacterial growth in 57.0% of the patients in the survival group and in 58.6% in the death group.The length of stay in the ED was 6.13 h (IQR: 4.75-8.68,p = 0.752) overall, and the total length of hospital stay was 14.18 days (IQR: 6.91-25.89)for the survival group and 3.24 days (IQR: 0.82-13.73,p < 0.05) for the death group.

Discussion
In this study, we investigated the utility of NT-proBNP as a biomarker for predicting in-hospital mortality in patients presenting to the emergency department with septic shock.The results revealed that NT-proBNP was a valuable predictive factor comparable to lactate, emphasizing its significance in predicting in-hospital mortality.
NT-proBNP is widely used in the ED for the diagnosis of heart failure.NT-proBNP, a metabolite of pro-BNP, is a prohormone secreted by myocardial cells 24 .The prohormone of brain natriuretic peptide (proBNP) is decomposed into the active metabolite brain natriuretic peptide and the inactive metabolite NT-proBNP.NT-proBNP has a longer half-life, so it remains in the bloodstream for a longer period of time 25,26 .Natriuretic peptides are www.nature.com/scientificreports/predominantly secreted during volume overload and cardiomyocyte stretching 27 .Although BNP is eliminated through various pathways, NT-proBNP is cleared exclusively by the kidneys [28][29][30][31][32] .Research comparing BNP and NT-proBNP is ongoing; however, there is still no consensus on which peptide is superior [33][34][35][36][37] , and the roles of these peptides have not been thoroughly studied 32,38 .
Although an increased plasma NT-proBNP level is primarily used as a biomarker for left ventricular (LV) dysfunction 26 , it is not necessarily specific to heart failure and is influenced by various conditions that cause myocardial strain and affect the clearance of NT-proBNP, including myocardial ischemia, arrhythmia, sepsis, shock, anemia, renal failure, pulmonary embolism, asthma, acute respiratory disease syndrome, and chronic obstructive pulmonary disease 32,36,[39][40][41][42] .NT-proBNP levels can increase in various situations, particularly in septic shock, a systemic inflammatory response accompanied by multi-organ damage, and there may be diverse interpretations as to whether the elevated levels are indicative of LV dysfunction or other diseases 32,[43][44][45][46][47] .
Since the underlying conditions can be difficult to ascertain in the ED, predicting the mortality rate in patients with septic shock using NT-proBNP levels, regardless of the underlying diseases, would be clinically useful.This analysis did not exclude patients with preexisting heart or kidney diseases.The survival and death Pip/tazo 75 ( Pip/tazo + meropenem 15 ( www.nature.com/scientificreports/groups included patients with various diseases, and the only significant difference between the two groups was stroke (p < 0.05, Table 1).In this study, lactate had an AUC of 0.678 (95% CI: 0.627-0.726),and NT-proBNP had an AUC of 0.648 (95% CI: 0.600-0.694)as predictors of mortality in patients with septic shock, and this finding is consistent with previous research results 32,36,[48][49][50][51][52] .There was no significant difference in the ROC curves between lactate and NT-proBNP (p = 0.6278, Table 4), indicating that NT-proBNP may serve as a substitute for lactate in predicting mortality in patients with septic shock when lactate cannot be used.
NT-proBNP could be a useful predictor of in-hospital mortality in patients with septic shock who present to the emergency department.

Limitations
This study has several limitations.Owing to its single-center design, caution should be exercised when extrapolating and applying the research findings on a broader scale.Additionally, the retrospective nature of this study introduced inherent limitations, particularly in defining sepsis.In the ED, patients with suspected sepsis are routinely tested for their initial lactate levels.However, lactate levels are not monitored after adequate fluid resuscitation, which does not fulfill the definition of septic shock recommended by Sepsis-3 1 .Table 3. AUROC, cut-off value, sensitivity, and specificity for hospital mortality of patients with septic shock.AUROC area under the receiver operating characteristic curve; CI confidence interval; LR likelihood ratio; NT-proBNP N-terminal pro-brain natriuretic peptide; BUN blood urea nitrogen; CRP C-reactive protein.

Figure 1 .
Figure 1.Flow chart of the study participants.ED Emergency department, qSOFA quick Sepsis-related Organ Failure Assessment, MAP mean arterial pressure, NT-proBNP N-terminal prohormone of brain natriuretic peptide.

Figure 2 .
Figure 2. Receiver operating characteristic (ROC) curve analysis of lactate (a), NT-proBNP (N-terminal prohormone of brain natriuretic peptide, (b), and BUN (blood urea nitrogen, (c) of patients with septic shock for in-hospital mortality.

Table 1 .
Baseline data of patients with septic shock presenting to the emergency department.Quantitative data are expressed as mean (± standard deviation) or median (interquartile range), and categorical data are presented as numbers (percentage).Student's t test or Mann-Whitney U test was used for continuous variable analysis, while the chi-squared test or Fisher's exact test was used for categorical variable analysis, as appropriate.DM diabetes mellitus; HTN hypertension; COPD chronic obstructive pulmonary disease; CKD chronic kidney disease; SBP systolic blood pressure; DBP diastolic blood pressure; HR heart rate; RR respiratory rate; BT body temperature.

Table 2 .
Comparison of laboratory test and management between survival and death group of patients with septic shock presenting to the emergency department.Quantitative data are expressed as mean (± standard deviation) or median (interquartile range), and categorical data are presented as numbers (percentage).Student's t test or Mann-Whitney U test was used for continuous variable analysis, while the chi-squared test or Fisher's exact test was used for categorical variable analysis, as appropriate.Pip/tazo Piperacillin/tazobactam, NE norepinephrine; VA vasopressin; DA dopamine; EP epinephrine.

Table 4 .
Pairwise comparison of the ROC curves.