Fluid intake-related association between urine output and mortality in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a complex response to pulmonary and non-pulmonary insults. This condition, which presents as severe hypoxemia and bilateral pulmonary infiltration, is associated with mortality rates of 30–40% [1, 2]. As pulmonary edema resulting from increased vascular permeability is a hallmark of ARDS [3], optimizing the fluid status is a fundamental concern in critical care practice.

Aggressive fluid resuscitation plays an important role in avoiding additional hemodynamic insults and maintaining adequate organ perfusion. However, considerable evidence indicates that a positive fluid balance (FB) may cause the extravasation of protein-rich fluids into the interstitial space and is strongly associated with poor outcomes in patients with ARDS [4‐6]. However, most of these studies focused mainly on the absolute FB volume, which may have led to biased conclusions. For instance, hypothetical patient A (fluid intake 2000 ml, fluid output 1000 ml) and patient B (fluid intake 5000 ml, fluid output 4000 ml) might have the same absolute FB volume but very different outcomes. Therefore, a new index that could better reflect the dynamic fluid status has become clinically important.

Two intervenable parameters in fluid management, the fluid intake (FI) [7] and urine output (UO) values [8], have been investigated. Multiple observational studies involving different cohorts have reported that an increased UO volume was independently associated with decreased mortality [9, 10]. A multicenter randomized controlled trial that compared conservative and liberal fluid strategies in patients with ARDS also reported that loop diuretics were more frequently used and the UO volume was higher in the conservative fluid group [7]. In that trial, the conservative fluid strategy was associated with improved lung function and a reduced duration of mechanical ventilation. However, the correlation between UO and the outcomes of patients with ARDS remains unclear.

Furthermore, the UO volume may be easily affected by the FI volume. Therefore, a simple evaluation of the association between UO and mortality that does not adjust for FI may be inappropriate. Here, we created a new index (UO/FI ratio) to reflect the dynamic fluid status and performed this secondary analysis to investigate the interactive associations among UO, FI, and mortality in patients with ARDS.

The data of 902 patients were available in the dataset downloaded from BioLINCC. Sixty-seven patients were excluded because of a lack of relevant records. Thus, 539 survivors and 296 non-survivors (835 total patients) were included in the final analysis. The overall mortality rate was 35.4%. Compared to non-survivors, survivors had a significantly higher UO volume within the 24-h period preceding the trial (27.9 ± 23.4 vs. 33.2 ± 25.8 mL/24 h, P = 0.003) and significantly lower FI volume (71.4 ± 56.8 vs. 63.4 ± 52.5 mL/24 h, P = 0.039). The maximum serum creatinine concentration was similar between survivors and non-survivors (1.59 ± 1.54 vs. 1.80 ± 1.47 mmol/L, P = 0.058). The detailed baseline characteristics and comparisons are listed in Table 1.

With this study, we aimed mainly to direct attention to the dynamic fluid status rather than the absolute fluid management volume. Here, we used the UO/FI ratio to reflect a patient’s ability to excrete excess administered fluids. We determined that for patients with a UO/FI ≤0.5, an increase in the UO/FI was significantly associated with decreased mortality. However, this association was non-significant for those with a UO/FI > 0.5. Furthermore, we also found that the UO/FI ratio significantly influenced the association between UO and mortality in ARDS. Moreover, the association between UO and mortality was significant only among patients with a UO/FI ratio ≤ 0.5. Therefore, this study offers novel insights into the complex interactions among UO, FI, and mortality in ARDS.

Appropriate fluid management is critical to the overall management of patients with ARDS, as pulmonary edema resulting from increased capillary permeability is a characteristic feature [3]. Several retrospective studies [5, 6] reported that both early and late increased fluid accumulation are significantly associated with poor outcomes in ARDS. Accordingly, recent investigations have focused on strategies to limit FI and increase the fluid output, with the aim of alleviating these poor outcomes [7, 13, 14].

In 2006 [7], the ARDS Network compared the efficacy of liberal and conservative fluid strategies and found that conservative fluid administration (more loop diuretics and higher UO volume) was shown to improve lung function and reduce the duration of mechanical ventilation. In another RCT, Martin et al. [15] found that when compared to a placebo, albumin and furosemide combination therapy resulted in a significantly higher UO during the intervention period, which was associated with an improved fluid balance, oxygenation, and hemodynamics in hypoproteinemic patients with acute lung injury. However, as both the diuretic [14, 15] and non-diuretic [16, 17] effects of furosemide may be responsible for the improved outcomes, the direct association between UO and mortality in ARDS cannot be inferred from these trials.

Multiple observational studies have demonstrated an independent association of increased UO with decreased mortality in unselected critically ill patients [9] or in patients with acute kidney injury [10]. In an observational study of 81 patients with ARDS who were receiving extracorporeal membrane oxygenation support, Hsiao et al. [18] found that the UO within the initial 24 h after the commencement of extracorporeal membrane oxygenation support, the mean arterial pressure, and the platelet count were independent risk factors for hospital mortality. Indeed, a decreased UO may indicate low renal perfusion and consequent fluid overload, which in turn contributes to subsequent organ dysfunction [8]. Nevertheless, it remains unclear whether these findings are translatable to regular ARDS patients, given the remarkable heterogeneity among these cohorts. Furthermore, a simple evaluation of the association between UO and mortality that is not adjusted for FI is insufficient. For instance, the clinical outcomes of two hypothetical patients with a similar UO volume of 1000 ml, depending on the FI.

In the current study, we observed a linear correlation between UO and the probability of hospital mortality. However, after adjusting for FI, we noticed that this association between UO and mortality was significant only in patients with low UO/FI ratios. We further identified a non-linear association between the UO/FI ratio and mortality. To some extent, these findings suggest a point of equilibrium between UO and FI, and also raise some new questions. For instance, would a patient with a low UO/FI ratio benefit from an increase in the fluid intake as guided by the UO/FI? Further, would the benefits of diuretics remain significant in patients with high UO/FI ratios? Of course, the underlying mechanisms, particularly with regard to the cut-off value, cannot be inferred due to the retrospective nature of this study. We speculate that the low UO/FI ratios imply some level of decompensatory organ function, such as cardiac failure, kidney failure, or unstable hemodynamics. However, the ability to excrete a greater UO volume may suggest relatively better organ function and less fluid accumulation, and may thus explain why a greater UO volume was associated with improved mortality. The cut-off value of 0.5 may serve as an indicator of the boundary between decompensatory and compensatory organ function and fluid accumulation. Hence, in patients with the ability to achieve high UO/FI ratios (> 0.5), the association between UO and mortality would not be significant. Further studies are needed to validate our hypothesis and re-evaluate the heterogeneous effects of fluid strategies, such as fluid restriction and diuretic use, in patients with different UO/FI ratios.

Our study had several advantages. First, all data were extracted from a rigorously designed multicenter trial, which guaranteed the accuracy of the data. Second, in contrast to previous studies, both UO and FI were used as continuous variables in our study (the OR was small, as it only represented the change in odds per UO or FI unit increase [1 mL/kg/24 h]), which maximized the statistical power. Third, to the best of our knowledge, this is the first study to report the UO/FI ratio, which may provide a better reflection of the fluid status than the UO alone. Further studies are needed to validate our findings.

Several limitations of our study should also be mentioned. First, we included as many potential confounders as possible, but could not exclude residual confounding bias. For instance, the interactive effects between diuretics and the UO/FI ratio could not be evaluated in this study because the dataset did not include diuretic records. Second, we only analyzed fluid records obtained within the 24-h period preceding the original trials. Therefore, it remains unclear whether the observed association would remain consistent across different time intervals. Third, the original study included only patients under invasive mechanical ventilation support, which restricts the applicability of our findings. Finally, the retrospective nature of the study limited our ability to determine a causal relationship between the UO volume and mortality. For instance, a higher UO volume may be an indicator of better kidney function, rather than a determinant of mortality. Thus, additional investigation is needed to determine whether strategies designed to increase the UO could improve the clinical outcomes of patients with ARDS.

In conclusion, in patients with ARDS, an increased UO was associated with decreased mortality. However, this association was influenced by the UO/FI ratio, and was only significant in the subgroup with UO/FI ratios of ≤0.5. Further studies are needed to validate and expand our findings.