In critical illness including sepsis, excessive sympathetic stress has adverse effects on multiple organs, especially on the heart (1–3). The detrimental effects on the heart comprise tachycardia, tachyarrhythmia, impaired diastolic function, myocardial ischemia, stunning, apoptosis, and necrosis. Tachycardia and atrial fibrillation (AF) were shown to be independent predictors of poor outcomes in critically ill patients (4,5). One recent report indicated that heart rate control with esmolol significantly improved mortality in septic shock patients (6). Moreover, it has been previously reported that new-onset AF might be associated with increased morbidity and mortality in septic patients (7). These reports implied that tachycardia and new-onset AF were related to myocardial damage in sepsis through supply-demand imbalance of oxygen (8) and inflammatory processes (9).
B-type natriuretic peptide (BNP) is a cardiac hormone secreted from the membrane granules of ventricles in response to volume expansion and pressure overload (10). The N-terminal peptide fragment of BNP precursor, N-terminal pro-B-type natriuretic peptide (NT-proBNP), also circulates in the plasma without known physiological activity (11). Both BNP and NT-proBNP were shown to be strong predictors of cardiovascular events (12,13). Several studies showed that both BNP and NT-proBNP were significantly elevated in septic patients (14,15). Moreover, recent observational studies demonstrated elevation of BNP was closely associated with increased morbidity and mortality in septic patients (16–18). In addition, BNP and NT-proBNP have been suggested as reliable biomarkers for identification of patients with cardiac dysfunction during sepsis (16,17,19). However, no study has evaluated the relationship between hemodynamic profiles of septic patients and these circulating cardiac biomarkers (i.e., BNP and NT-proBNP) thus far.
This prospective observational study was conducted in a cohort of critically ill adult patients who were treated in a noncardiac intensive care unit (ICU). The aim of this study was to elucidate whether hemodynamic abnormalities such as tachycardia and new-onset AF were associated with elevation of NT-proBNP and the mortality in septic and nonseptic patients.
PATIENTS AND METHODS
Patient population and study design
In this single-center observational study, we prospectively enrolled patients who were admitted to the mixed medical/surgical ICU of the University of Tokyo Hospital between October 2012 and March 2015. All adult patients over the age of 20 were eligible for enrollment, and the patients with pregnancy, with chronic heart disease (previously known left or right ventricular dysfunction with an ejection fraction <50%, severe valvulopathy, or chronic arrhythmia), or with previously known chronic kidney disease defined as a serum creatinine level of more than 2.0 mg/dL were excluded because NT-pro BNP levels were difficult to interpret in those population. The study protocol adhered to the Declaration of Helsinki and was approved by the institutional review board of the University of Tokyo. Informed consent was obtained from each participant or the participant's legal representative. The diagnosis of sepsis was based on the definition of the American College of Chest Physicians/Society for Critical Care Medicine (20).
The following clinical variables were evaluated: age, sex, diagnosis for ICU admission, and sequential organ failure assessment (SOFA) score at ICU admission. The ICU length of stay, in-hospital mortality, and 28-day overall mortality were also documented. In addition, information on agents used for continuous sedation and analgesia, antiarrhythmics, vasopressors, and inotropic agents administered at ICU admission were obtained from the medical records.
We analyzed arterial blood samples to determine the ratio of arterial oxygen partial pressure to fraction of oxygen in inspired air (PaO2/FiO2 ratio) as a marker for oxygenation, standard hematology, biochemistry, and levels of two cardiorenal biomarkers, NT-proBNP and neutrophil gelatinase-associated lipocalin (NGAL). NGAL is an emerging biomarker of acute kidney injury (AKI). The Triage NT-proBNP Test and the Triage NGAL Test (Alere Medical, San Diego, Calif) were used for plasma NT-proBNP and NGAL measurements, respectively.
Heart rate and rhythm of study patients were documented hourly on nursing flow sheets. In a previous study, an initial heart rate under 106 bpm, which was recorded at the time of ICU admission within 3 h of shock, was shown to be a significant predictor of survival in septic shock patients (21). Accordingly, a heart rate over 100 bpm was defined as tachycardia in our study. Hypovolemia and lack of sedative agents might contribute to the development of tachycardia. In this study, the average heart rate values during the initial 4 h of ICU were documented as heart rate at admission, as appropriate sedation and volume resuscitation that had started shortly after ICU admission were expected to be effective within 4 h. New-onset AF was defined as development of AF in the ICU in a patient with no prior history of AF, as determined by review of medical records.
Continuous variables were presented as means ± SD or median (interquartile range), and categorical variables were presented as percentages. Continuous data were compared using Student t test or Mann-Whitney U test. Categorical data were compared using chi-square test or Fisher exact test. First, we compared the impact of hemodynamic abnormalities on 28-day overall survival using log-rank test and constructed multivariate Cox proportional regression models to evaluate whether hemodynamic profiles could be independent determinants of 28-day all-cause mortality. The following parameters reportedly related to mortality in septic patients were adjusted (5,22): age, sex, serum creatinine, serum lactate, the use of norepinephrine, PaO2/FiO2 ratio, SOFA score, and treatment factors influencing sympathetic tone and heart rate (i.e., vasopressors and inotropic agents, continuous sedation, continuous analgesia, and antiarrhythmics (4)). The parameters that showed significant association by univariate analyses were included in multivariate Cox regression models. Then, multivariate linear regression analyses with NT-proBNP and NGAL as dependent variables were conducted to examine the association of hemodynamic abnormalities with NT-proBNP and NGAL. Adjusted parameters, which were proposed to be associated with NT-proBNP elevation, were the following (16,17,22): age, sex, serum creatinine, PaO2/FiO2 ratio, SOFA score, the use of norepinephrine, and the occurrence of new-onset AF and treatment factors influencing sympathetic tone and heart rate. The potential confounding factors for NGAL included age, sex, the use of norepinephrine, nonrenal SOFA score (SOFA score without the renal component), history of hypertension, diabetes mellitus, liver cirrhosis, the use of drugs with nephrotoxic potential (such as nonsteroidal anti-inflammatory drugs, aminoglycosides, angiotensin converting enzyme inhibitor, angiotensin II receptor blocker, and diuretics) (23,24), and treatment factors influencing sympathetic tone and heart rate. Only parameters that were significantly associated with NT-proBNP or NGAL in univariate linear regression analyses were included in multivariate linear regression models. NT-proBNP, NGAL, serum lactate, serum creatinine concentration, and PaO2/FiO2 ratio were entered into these models as log-transformed variables using the natural logarithm to the base e to account for skewed distribution.
The cardiorenal biomarker cutoff points for discriminating sepsis and tachycardia at ICU admission were assessed using receiver-operating characteristic (ROC) curve analysis. The cutoff points were determined at which the Youden index (sensitivity + specificity − 1) (25) was maximized.
The JMP Pro software (version 11.0.0; SAS Institute, Cary, NC) was used for all statistical analyses, and P < 0.05 was considered statistically significant for all tests.
Three hundred sixty-three patients were admitted to the ICU during the study period. Ninety-six patients were excluded: 90 patients had chronic heart and/or chronic kidney disease and 6 patients had missing data. Finally, 267 patients (septic: n = 95, and nonseptic: n = 172) were enrolled (Fig. 1).
Table 1 shows the baseline characteristics and outcomes of enrolled patients. The septic patients were significantly older than the nonseptic patients, whereas there was no significant difference in sex ratio between the groups. The sepsis group was composed mainly of patients with critical medical illness, whereas the nonsepsis group contained more patients with surgical critical illness and multiple trauma. At ICU admission, heart rate was higher in the sepsis group, whereas new-onset AF occurred in low frequency in both groups (6.3% in the sepsis group vs. 2.9% in the nonsepsis group, not significant). More severely ill patients were in the sepsis group than in the nonsepsis group; more patients were treated with norepinephrine and had higher serum creatinine, lower PaO2/FiO2 ratio, higher SOFA score, and higher in-hospital mortality. Levels of NT-proBNP and NGAL were significantly higher in the sepsis group than in the nonsepsis group.
Table 2 compares treatment characteristics influencing sympathetic tone and heart rate between the nontachycardia and tachycardia group. Although there was no difference in all the treatment factors in septic patients, patients with tachycardia were more likely to receive infusion of dopamine and patients without tachycardia were more likely to receive continuous sedation only in nonseptic patients.
Impact of hemodynamic abnormalities on mortality in septic and nonseptic patients
Figure 2 shows the unadjusted Kaplan-Meier curve analysis of 28-day overall survival in tachycardia and nontachycardia groups in septic patients. Overall survival was lower in the tachycardia group. In contrast, the impact of new-onset AF on 28-day overall survival was not significant by the Kaplan-Meier curve analysis. We next compared the presence of tachycardia and the other clinical parameters selected a priori according to 28-day mortality (see Table, Supplemental Digital Content 1, http://links.lww.com/SHK/A406, which compares patient characteristics according to 28-day mortality in nonseptic and septic patients). Only tachycardia, PaO2/FiO2 ratio, and serum creatinine level were significantly associated with 28-day mortality in the univariate analysis. All the parameters were shown to be independent determinants of 28-day overall survival of septic patients in the multivariate Cox regression model (Table 3).
In the nonsepsis group, the unadjusted Kaplan-Meier curve analysis showed that tachycardia contributed to decreased 28-day overall survival (Fig. 3). However, new-onset AF failed to show a significant association with the 28-day overall survival. We next evaluated the clinical determinants of 28-day overall survival, similar to that performed in septic patients. Multivariate Cox regression analysis demonstrated that tachycardia failed to independently predict overall survival in nonseptic patients (see Table, Supplemental Digital Content 2, http://links.lww.com/SHK/A407, which demonstrates the result of multivariate Cox regression analysis for independent predictors of 28-day overall survival in nonseptic patients).
Association of hemodynamic abnormalities with cardiorenal biomarkers
Figure 4 shows the levels of NT-proBNP and NGAL at ICU admission stratified according to the presence of tachycardia in sepsis and nonsepsis groups. NT-proBNP and NGAL levels were significantly higher in patients with tachycardia only in the sepsis group. In addition, the new-onset AF did not have a significant impact on NT-proBNP and NGAL levels (see Figure, Supplemental Digital Content 3, http://links.lww.com/SHK/A408, which compares the cardiorenal biomarkers between the AF and sinus rhythm (SR) groups in septic and nonseptic patients). Among tachycardia and the other confounding factors of NT-proBNP elevation, tachycardia, serum creatinine, PaO2/FiO2 ratio, and the use of norepinephrine were significantly correlated with NT-proBNP values in septic patients by univariate linear regression analysis. These clinical determinants of NT-proBNP elevation were further included in multivariate linear regression analysis. Tachycardia, serum creatinine level, and PaO2/FiO2 ratio showed an independent association with NT-proBNP in septic patients (Table 4). However, univariate and multivariate linear regression analysis examining the association between tachycardia and NGAL elevation revealed that tachycardia was not an independent determinant of NGAL elevation (see Table, Supplemental Digital Content 4, http://links.lww.com/SHK/A409, which demonstrates the result of univariate and multivariate linear regression analysis for independent factors of NGAL rise in septic patients).
ROC-derived cutoff points of cardiorenal biomarkers and prediction of adverse outcomes
By ROC curve analysis, the area under curve (AUC-ROC) and cutoff points of NT-proBNP and NGAL for detecting sepsis and tachycardia at ICU admission were calculated. Table 5 shows AUC-ROC, cutoff points, sensitivity, specificity, and likelihood ratio of NT-proBNP and NGAL. We applied the term “NT-proBNP (−)” or “NT-proBNP (+)” to indicate below or above cutoff points. In the same way, we defined the term “NGAL (−)” or “NGAL (+).” In the study cohort, the patients were categorized into four groups: NT-proBNP (−) NGAL (−), NT-proBNP (+) NGAL (−), NT-proBNP (−) NGAL (+), and NT-proBNP (+) NGAL (+). Twenty-eight-day mortality in the four groups was shown in Table 6. The highest 28-day mortality was observed in the NT-proBNP (+) NGAL (+) group.
Excessive sympathetic stress has recently been recognized to have detrimental impact on multiple organ systems and prognosis in septic patients. Several reports demonstrated that tachycardia was associated with poor outcomes in sepsis (6,21), though tachycardia is an important compensatory mechanism to maintain perfusion in response to intravascular volume depletion. This study demonstrated that a heart rate above 100 bpm at ICU admission had a significant impact on all-cause mortality in septic patients treated in a mixed ICU. In addition, among numerous clinical parameters evaluated, tachycardia was independently associated with a cardiac biomarker NT-proBNP, which potentially reflects cardiac injury.
There is increasing basic research evidence on the underlying mechanism by which tachycardia contributes to BNP elevation. Rademaker et al. (26) investigated the response of natriuretic peptides (i.e., atrial natriuretic peptide [ANP] and BNP) to tachycardia induced by acute and chronic left ventricular (LV) pacing in sheep. The study showed that acute and chronic increases in LV pacing rates induced significant reduction in left ventricular systolic pressure (LVSP), mean arterial pressure, and cardiac output and increases in left atrial pressure, in association with elevated plasma ANP and BNP levels. Moreover, by using a dog model, de Pauw et al. (27) demonstrated that short-term (48 h) rapid ventricular pacing impaired contractile function as reflected by the decrease in LVSP and by the increase in LV end-diastolic pressure. These experiments implicated that the development of tachycardia-induced cardiac dysfunction is associated with intracellular functional remodeling of myocardium to counteract calcium overload provoked by rapid pacing. However, the exact mechanism remains uncertain. Further investigations are needed to clarify unrevealed mechanisms for natriuretic peptide elevation in the clinical.
Recently, Morelli et al. (6) reported that maintaining heart rate within a target range of 80 to 95 bpm using esmolol was associated with improved hemodynamic parameters and 28-day overall survival in septic shock patients. They proposed that esmolol restored ventricular end-diastolic volume by lowering heart rate and decreased myocardial workload and oxygen consumption, thereby ameliorating the development of myocardial ischemia and cardiac dysfunction. Conversely, noncardiac impact of esmolol may also have beneficial effects. In animal septic shock models, Kimmoun et al. (28) showed that esmolol improved cardiac and vascular function via its anti-inflammatory effects. Whether heart rate control alone plays an important role in improved cardiac function and prognosis of sepsis patients remains to be determined.
In this study, tachycardia was a significant and independent predictor of 28-day overall survival only in the septic patients, which is compatible with Parker's report (21). Although the association of heart rate with mortality was reported in a number of observational studies (29–31), our results in nonseptic patients are not in line with those previously reported. Furthermore, a significant association between tachycardia and NT-proBNP elevation was detected only in septic patients. Numerous cytokines including tumor necrosis factor-α and interleukin-1β that were elevated in septic patients were suggested to have cardiodepressant properties (32). A synergistic effect of tachycardia and circulating cytokines might contribute to NT-proBNP elevation in septic patients. However, because of unbalanced baseline characteristics between nonseptic patients and septic patients, the difference in association of tachycardia with NT-proBNP between these groups might be attributed to other underlying pathophysiology of the acute illness other than sepsis.
Cardiorenal syndrome is a distinct clinical entity defined by the pathophysiological interaction between cardiac and renal dysfunction through a complex combination of neurohormonal mechanisms (33). The mechanisms responsible for sepsis-induced cardiorenal syndrome are poorly understood; however, a systemic hyperinflammatory state precipitated by humoral mediators might have more deleterious effects than hemodynamic insults on both organs (34,35). NGAL, a recently developed AKI biomarker, was specifically elevated in septic AKI cases (24). Thus, we evaluated whether hemodynamic abnormalities in septic patients contributed to AKI development via cardiorenal interaction using NGAL as an AKI biomarker. Our results indicated that although NGAL was significantly elevated in the tachycardia group compared with the nontachycardia group, tachycardia failed to be an independent determinant of NGAL elevation by multivariate linear regression analysis in septic patients. Further evaluation is necessary with the inclusion of other renal parameters to elucidate the role of cardiorenal syndrome in sepsis.
Our study showed that 28-day mortality in the study patients was increased remarkably when both NT-proBNP and NGAL were elevated. This finding indicated that the combination of cardiorenal biomarkers (i.e., NT-proBNP and NGAL) have potential for stratifying ICU patients by predicting adverse outcomes. In ICU patients with heterogeneous background, using combination of cardiorenal biomarkers for risk stratification might be beneficial in the clinical setting. We determined biomarker cutoff points for detecting sepsis or tachycardia at ICU admission based on Youden index in ROC curve analysis, which is a common summary measure of the ROC curve representing the maximum potential effectiveness of a marker (25). Further investigation is necessary using other cutoff points that have higher sensitivity or specificity compared with those used for this study.
Several limitations might affect our findings. First, this study was conducted at a single center. The number of enrolled patients was not sufficient to investigate whether new-onset AF was significantly associated with NT-proBNP. In septic patients, no significant difference in NT-proBNP levels could be detected between the new-onset AF and SR groups. Future studies with larger cohorts in multicenter ICUs should be conducted to confirm and expand our findings. Second, heart rate, rhythm, and cardiorenal biomarker measurements were recorded only at ICU admission. Repeated measures data analysis will provide superior insight into associations between hemodynamic abnormalities and NT-proBNP. Third, this observational cohort study could not determine whether tachycardia was a causative factor in NT-proBNP elevation and increased mortality. Fourth, although we performed fluid resuscitation for all patients during the early unresuscitated shock stage based on ICU physicians’ decision shortly after ICU admission, there were no definitive indicators to determine correctly whether fluid volume was adequate.
Finally, we acknowledge that we could not evaluate direct relationship between tachycardia and cardiac dysfunction because cardiac function was not assessed with echocardiography in our study. NT-proBNP as a biomarker of myocardial dysfunction during sepsis remains controversial. Plasma BNP levels were previously reported to be elevated in septic patients with myocardial dysfunction, as assessed by echocardiography early in the clinical course of sepsis (16,17). Moreover, Hartemink et al. (19) showed that NT-proBNP was an independent marker of systolic cardiac dysfunction detected by transpulmonary thermodilution and pressure measurement, irrespective of the filling status, in critically ill septic patients. In contrast, Papanikolaou et al. (22) reported that not myocardial dysfunction but the severity of critical illness might be the main determinant of BNP elevation in septic patients. They found that pulmonary artery catheter-derived LV systolic workload, considered as a less load-dependent index of left ventricular contractility, failed to demonstrate an independent association with BNP elevation. However, in these studies, the study populations were relatively small. Thus, further studies are needed to evaluate the diagnostic value of BNP and NT-proBNP in a larger cohort of septic patients. As both chronic heart and kidney diseases can cause NT-proBNP elevation, patients with those comorbidities were excluded in our study. However, these patients account for a sizable portion of ICU admissions. The association of hemodynamic profiles with NT-proBNP in patients with these comorbidities needs to be determined.
In conclusion, our study demonstrated that tachycardia at ICU admission was significantly and independently associated with NT-proBNP elevation and poor prognosis in septic patients. Further investigation is necessary to evaluate the beneficial effect of heart rate control on cardiac function and survival in septic patients.
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Atrial fibrillation; biomarkers; N-terminal pro-B-type natriuretic peptide; prognosis; sepsis; tachycardia
Supplemental Digital Content
© 2016 by the Shock Society