In this study, the BNP and GEDI in patients with sepsis undergoing invasive ventilation were mildly but significantly correlated when GEDI was considered a continuous variable.
GEDI is considered to be a measure of the systemic fluid volume, because GEDI is calculated by dividing the global end-diastolic volume (GEDV) by the body surface area, which indicates the intrathoracic and pulmonary vascular blood volume (11). In contrast, BNP, a hormone synthesized mainly by the ventricles, has been used as a biochemical marker that sensitively reflects the degree of ventricular load, because its secretion is increased by ventricular load, causing a rise in its blood concentration(24). BNP is a superior auxiliary diagnostic method for heart failure, because plasma BNP concentrations correlate well with the hemodynamics, and BNP reflects the left ventricular load precisely(25). In this study, GEDI was elevated due to the increased circulating plasma volume in response to the acute phase of sepsis infusion load. Similarly, BNP was also elevated in response to the left ventricle progression in response to the infusion load. These facts could indicate that BNP may be elevated in the acute phase of sepsis as well similar to the pathogenesis of heart failure, reflecting the excess fluid volume in the acute phase of sepsis.
However, the correlation coefficient between BNP and GEDI was 2.5; the value was small and the correlation was mild, which may render it difficult for use in clinical practice. There could be three possible reasons for the small correlation coefficient: first, as shown in Fig. 2, the median values of GEDI in this study over the three days of ICU stay remained within the upper limit of normal (850 ml/m2). Therefore, it could be possible that BNP was not secreted and was thus not sufficiently elevated due to the insufficient increase in blood volume in the left ventricular cavity, and the lack of expansion of the left ventricular cavity associated with the infusion load. The second reason, as noted in the early goal-directed therapy (EGDT), the acute phase of sepsis requiring large amount of volume infusion is generally considered to be approximately 6 hours from the diagnosis of sepsis(26). In this study, the inclusion of data up to 72 hours when volume infusions are no longer needed and GEDI and BNP were no longer elevated, might have resulted in a small correlation coefficient and mild correlation. The third reason: BNP rises within 1 hour of stimulation and has a biological half-life of 20 minutes in the body(17). Since the GEDI and BNP measurements in this study were performed every 6 hours, it is possible that even though the left ventricular cavity was sufficiently enlarged by volume infusion to cause an increase in BNP, the very short half-life of the BNP caused a decrease at the time of measurement, which might have resulted in a small and mild correlation coefficient.
Considering these reasons, it may be possible to obtain larger regression coefficients and stronger correlations by shortening the measurement period of BNP to within 6 hours from starting the treatment and shortening the measurement interval to every hour or so.
Since the present study has revealed a possible association between BNP and GEDI, this study could guide further studies evaluating the usefulness of BNP as an indicator of over-infusion, using the upper limit of GEDI as a cutoff value as the index of over-infusion. Although this study is a pilot study, if further studies show that BNP can be an indicator of over-infusion, a minimally invasive, simple, and quick assessment of over-infusion would be possible. This finding could lead to avoidance of over-fusion, which might lead to a reduction in the adverse events, including increased mortality, and thus might have tremendous clinical benefit.
However, there are several limitations in this study. First, as noted in the EGDT, the acute phase of sepsis in which we need large volume of infusion is generally considered to be approximately 6 hours from the diagnosis of sepsis(26). Because the GEDI and BNP assessments in this study were conducted at 0, 24, 48, and 72 hours after ICU admission, when volume infusions were no longer needed, and GEDI and BNP were no longer elevated, this might have contributed to a small correlation coefficient and mild correlation. Second, the median SAPS II score was 53 in this study, which is not suggestive of the most critically ill patients. In addition, the median infusion volume within 24 hours from ICU admission was 4492 ml and the median GEDI time series were all within the upper limit of normal for GEDI (850 ml/m2). These facts suggest that the patients in this study were not severely ill requiring large amount of infusion; thus, the increase in GEDI and BNP was small, and neither GEDI nor BNP was elevated, and thus, no correlation was found. Third, the half-life of BNP is 20 minutes, and even if BNP was elevated, we could not record an increase in BNP by the 6-hourly measurements. Fourth, due to insufficient number of analyzed patients, we might not be able to detect significant differences when using a generalized linear mixed-effects model with GEDI of 850 ml/m2 as the cutoff for the two groups. Fifth, the results of this study may be biased because the patients with severe anemia or acute kidney injury, in whom errors in BNP and GEDI measurements can occur, were not excluded.
Nevertheless, this pilot study suggests that GEDI and BNP may be correlated when GEDI is considered a continuous variable. However, further studies are warranted to increase the number of patients and obtain more frequent BNP measurements within the first six-hours.