The present study demonstrated that increased cumulative %FO was associated with higher mortality and shorter VFDs from the early phase of critical illness; notably, the cumulative %FO was significantly associated with mortality from the 27th hour of ICU admission and the association between %FO and VFDs had significance from the first hour of ICU admission and lasting for up to 72 hours. Clustering analysis by %FO transition illustrated that the increased %FO in the first 24 hours and an exceeding %FO of > 10% at 72 hours was associated with high mortality.
Previous studies reported that the increased cumulative fluid balance on day 3 was associated with higher mortality in critically ill patients with AKI or who received invasive mechanical ventilation [11, 12]; investigation in septic patients suggested that fluid balance during hours 24 to 48 after ICU admission was associated with hospital mortality whereas there was no association in the first 24 hours [4]. Our analysis of the association between hourly FO data and mortality suggested that the exact timepoints of FO should be earlier than that of previous reports, and it should be considered in the fluid resuscitation management of critically ill patients.
FO impairs organ functions due to edema [19, 20]. Pulmonary edema leads to impaired gas exchange and hypoxemia, which makes a requirement for ventilatory support [21]. A previous investigation in patients who received mechanical ventilation reported that increased fluid balance on day 3 was significantly associated with shortened VFDs [12], which is consistent with our results. A noteworthy finding of the present study is that the %FO was associated with VFDs from the first hour of ICU admission. This indicates that physicians need to pay attention to controlling fluid balance as much as possible even in the initial phase of treatment.
In using hierarchical clustering analysis, we found that a negative %FO during the first 24 hours was associated with decreased mortality, whereas mortality was increased as %FO was higher in the positive range. Added to the association of mortality with fluid balance at this period, a larger increase of FO in the following period was associated with increased mortality. In addition, we confirmed that a cumulative %FO > 10% at 72 hours was associated with higher mortality. A previous study of patients who received invasive mechanical ventilation reported that the patients who could achieve to have a negative fluid balance on day 3 by deresuscitative measures had lower mortality than the patients who had positive fluid balance [12]. In addition, a previous study in patients with AKI demonstrated that the patients who had cumulative %FO > 10% during the first 3 days of treatment had high mortality of 49.1% [11]. In this study, mortality in clusters 5–8, where the patients had %FO > 10%, was 31–71% (Fig. 3). Our results are consistent with those of previous reports, and our clustering analysis with visualization may contribute to clarifying the association.
This study has several limitations. First, since this is a single-center retrospective study, it may have selection bias. However, we screened more than 8000 patients and included over 1000 patients in this study, which may contribute to generalization of the patients and reducing the bias. Second, we could not differentiate the type of administered fluid. Crystalloids or colloids may have different roles and result in different outcomes [22, 23]. Third, we did not consider the administration of diuretic agents. Further study is required to observe the impact of diuretic agents on the outcomes.
In the conclusions, a higher %FO was associated with increased mortality and shortened VFDs. These associations were seen from an earlier phase than previously reported. Fluid balance should be carefully controlled in critically ill patients with AKI, even during the initial treatment phase.