The interactive effects of input and output on managing fluid balance in patients with acute kidney injury requiring continuous renal replacement therapy

Fluid overload has been associated with aggravating renal dysfunction, an increase in length of intensive care unit (ICU) stay, and an elevation in mortality risk [1‐4]. Hence, negative fluid balance is regarded as an essential strategy to improve survival rates in critically ill patients, and continuous renal replacement therapy (CRRT) has been widely used for fluid regulation in critically ill patients with acute kidney injury (AKI) [5‐7]. However, there is no consensus on the optimal fluid management for such patients [8‐12]. Several recent studies revealed that an increase of cumulative fluid balance (CFB) was significantly associated with an increase in mortality risk in critically ill patients [13‐17], while Balakumar et al. showed that both positive and negative fluid balance were associated with higher mortality rates compared with even fluid balance [18]. Furthermore, Silversides et al. reported that active removal of fluid using RRT in critically ill patients was associated with less survival benefit compared with standard care [19‐21].

Fluid resuscitation for critically ill patients with AKI has both advantages and disadvantages. Fluid resuscitation can help keep patients hemodynamically stable, maintain renal perfusion, and prevent further ischemic injury due to ongoing renal dysfunction. However, accumulating interstitial fluid hinders oxygen delivery to cells from blood vessels and can lead to renal ischemia and multi-organ failure [9, 12, 22]. Thus, optimal management of fluid balance in patients with AKI, especially those requiring CRRT, still needs to be investigated. In addition, most physicians have focused on CFB, even though CFB is determined by the amount of input and output. However, there is still no definite answer for which strategies better benefit survival: does higher output translate into better clinical outcomes, or does lower input translate into better clinical outcomes. Therefore, in this study, we investigated the association between CFB, cumulative input and output amounts at 24-h and 72-h after initiation of CRRT, and mortality risk among patients with AKI receiving CRRT.

This study shows the effects of cumulative input and output on the impact of short-term (24-h) and relatively long-term (72-h) CFB on 7- and 28-day mortality risk among AKI patients undergoing CRRT. We found that both increases in short-term and longer-term CFB were significantly associated with increases in 7- and 28-day mortality risk, and the effect of CFB on mortality might be dependent on cumulative output.

The main concern in AKI patients undergoing CRRT is how to control their volume status [26, 27]. Several studies have examined this issue, and almost all suggested that fluid overload was significantly associated with increased mortality risk as well as aggravation of kidney function [2, 16, 28]. Although most studies have focused on a negative fluid balance in AKI patients with CRRT, physicians need to consider volume resuscitation, since it is crucial to restore and maintain hemodynamic stability in critically ill patients [29‐32]. To reduce CFB, physicians need to choose low fluid resuscitation and high removal of resuscitation as much as possible. We stratified the patients in this study into three groups based on 24-h and 72-h cumulative input or output tertiles to reveal the interactive effect of cumulative input or output on the impact of CFB on mortality. We found a big VIF between CFB and cumulative input/output, respectively, and it was difficult to adjust cumulative input and output to show the impact of CFB on mortality risk, independently. We also found that the increase in CFB was still significantly associated with an increase in mortality risk irrespective of the stratification of cumulative input, which suggests that removal of more fluid output may reduce the mortality risk. In contrast, when we performed Cox analysis for mortality after patients were stratified based on cumulative output, there was no significant association between CFB increase and mortality risk, which means that reduction of cumulative input might not decrease mortality risk.

Moreover, we also investigated the characteristics of the three patient groups stratified by their cumulative input and output at 24-h and 72-h after CRRT initiation (Additional file 1: Table S3). Especially, there were no significant differences in MAP, CCI, and SOFA scores among the three groups stratified by output amount, suggesting that fluid removal might be done irrespective of illness severity. Therefore, we do not think a higher rate of fluid removal is simply a marker of lower illness severity. Instead, more fluid removal could provide an indirect benefit against the oxygen-mismatched diffusion and distorted tissue architecture that originate from fluid overload and tissue edema. Taken together, we suggest that physicians need to pay closer attention to decreasing CFB, especially by increasing fluid removal, to improve the clinical outcomes of their AKI patients receiving CRRT.

Adequate fluid resuscitation is essential to restore tissue perfusion in critically ill patients with AKI [27, 33, 34], and fluid administration contributes to improve glomerular filtration [9]. Moreover, fluid administration is aimed to restore systemic blood pressure, a major determinant of renal perfusion pressure and cardiac output [35‐37]. In particular, patients with severe sepsis need adequate fluid resuscitation within 1 to 3 h of disease onset to overcome their hemodynamically unstable state [38, 39]. Thus, clinicians may try to administer more fluid to restore tissue perfusion and to improve disease course. However, fluid overload and tissue edema physiologically result in impaired diffusion of oxygen and metabolites, distorted tissue architecture, obstruction of capillary blood flow or lymphatic drainage, and disturbed cell-cell interactions. These processes subsequently contribute to progressive organ dysfunction. The patients in the current study were more likely to be overhydrated at CRRT start, and their severity scores (SOFA and APACHE II score) were higher than those in other studies [25, 40]. Thus, more removal of patient output seems to be more effective for a decrease in mortality compared with lower cumulative input, and interpretation of the current study should be made with caution. Generally, most AKI patients who require CRRT are critically ill and in an overhydrated condition [27, 41]. Moreover, effective circulating volume appears to be low in these patients [8]. Thus, we surmise that it might be more helpful to increase fluid removal than to decrease input. Furthermore, Murugan et al. [42] recently showed that higher ultrafiltration intensity (> 25 mL/kg/day) was associated with lower risk for mortality compared with lower ultrafiltration intensity (≤ 20 mL/kg/day) among critically ill patients with fluid overload who were undergoing CRRT. The authors suggested several reasons for the benefit of intensive removal. First, increase in cumulative output may reduce the risk of subsequent edema-related organ dysfunction [43]. Second, the increase in cumulative output by intensive net ultrafiltration may lead to better clearance of unknown molecules and contribute to better survival independently of fluid balance [44].

There are several limitations in the current study. First, this study was a retrospective study conducted in a single center with a relatively small sample size. Thus, selection bias was not completely avoidable, and these results may not be applicable to other ethnicities. Nevertheless, we assessed the power of our study sample size, and it was more than 80%, showing the robustness of our study sample size (Additional file 1: Table S4). In addition, previous studies with AKI patients undergoing CRRT were performed with sample sizes similar to ours [3, 45]. Moreover, this is the first study, to the best our knowledge, to reveal the interactive effect of fluid input and output in managing fluid balance for CRRT-treated AKI patients, so it can serve as precedent research for future prospective interventional studies with more patients that are needed to verify our study results. Second, we could not measure the effects of diet or drugs used or insensible water loss. However, most of these patients could not eat and nutritional support was provided via an infused solution for 72-h from CRRT start [only 28 (10.9%) patients were supplied with enteral nutritional fluid]. Third, physicians wanted to increase mechanical fluid removal when their patients could endure the increase in fluid removal, suggesting that patients whose removal was increased would experience better clinical outcomes. Several studies investigating the effect of fluid overload on mortality in critically ill patients have been performed, and most of these studies showed that a high CFB was significantly associated with increased mortality risk. However, it seems to be a case of the chicken and the egg. It can be difficult to increase fluid removal when patients are hemodynamically unstable, which suggests that greater illness severity, rather than increased CFB might be leading to worse clinical outcomes. In this study, however, we tried to adjust the severity indices, such as MAP, CCI, and SOFA score, to exclude the effect of those factors on mortality and we found that high CFB was still significantly related to an increase in 7- and 28-day mortality independently of the severity indices. Taken together, we surmise that fluid removal itself might provide an indirect benefit for clinical outcomes by improving tissue oxygenation, not just that a higher rate of fluid removal is a marker of lower severity of illness. Fourth, we arbitrarily stratified these patients into three groups based on cumulative input and/or output to examine the interaction of input and/or output on CFB impact on mortality. However, we investigated the interaction between CFB and cumulative input and output and found that VIF was too large to be adjusted with CFB. Thus, we decided to analyze the effect of cumulative input and output on the impact of CFB on mortality after stratifying the patients. Finally, we used eGFR as a marker of the patients’ renal function status, even though it is not a valid reflection of renal function in an acute setting. In this study, we could not have evaluated baseline kidney function with gold standard methods for GFR measurement such as inulin clearance, so we only used calculated eGFR values with MDRD equation. Further study is needed to accurately compare baseline kidney function measured by gold standard methods. Despite these limitations, this study reports robust clinical findings for the effect of an increase in short-term and longer-term CFB on mortality risk and the dependence of CFB on cumulative output.

In conclusion, an increase in CFB was significantly associated with an increase in mortality risk in AKI patients undergoing CRRT, irrespective of cumulative period. Moreover, the impact of CFB on mortality might be dependent on cumulative output. Although a prospective interventional study with a larger number of patients will be needed, this study revealed that physicians need to decrease the CFB of CRRT patients as much as possible and to consider increasing the amount of fluid removal.