Fluid balance, intradialytic hypotension, and outcomes in critically ill patients undergoing renal replacement therapy: a cohort study

Acute kidney injury (AKI) occurs commonly in critical illness, with 4 to 10% of patients admitted to the intensive care unit (ICU) requiring renal replacement therapy (RRT) [1]-[3]. In recent studies, the mortality of ICU patients with AKI requiring RRT has been reported to be 40 to 50% [1],[4]. Specific therapeutic options for AKI are lacking, and emphasis has traditionally been placed on maintenance of renal perfusion using intravenous fluids, inotropes, and vasopressors. Fluid loading is advocated, particularly in sepsis-related AKI, to treat possible hypovolaemia, improve cardiac output, and maximise renal blood flow [5]. This practice is largely unsupported by evidence and has been challenged by observations that renal blood flow in sepsis may be normal, elevated or decreased [1],[4],[6], that the renal resistive index, a measure of renal vascular tone, is unchanged in response to fluid challenge in septic patients [5],[7], and by numerous observational studies demonstrating an association between fluid overload and mortality in critically ill adults and children with AKI [1]-[4],[8]-[12]. It is unclear whether this association reflects confounding by greater severity of illness in patients whose intravenous fluid requirements are higher or in whom efforts to remove fluid are poorly tolerated, or whether it simply reflects variation in the timing of RRT initiation. However, variation in the timing of RRT initiation is unlikely to be the sole explanation for the association between fluid overload and mortality, since it has been demonstrated in cohorts that included AKI patients managed without RRT [9],[10] and has been noted at time points other than at RRT initiation [10]. It is also unclear whether treatment with diuretics or ultrafiltration is effective in modifying this relationship.

We conducted a cohort study to investigate the relationship between fluid balance and outcome in critically ill patients with AKI requiring RRT. We hypothesised that positive fluid balance and intradialytic hypotension during the first seven days after RRT initiation would be associated with both mortality and RRT dependence at hospital discharge.

A total of 492 patients, of whom 299 (60.8%) were male, met criteria for inclusion in the study (Figure 1). The mean (SD) age was 62.9 (16.3) years, the mean (SD) SOFA score at ICU admission was 12.1 (4.2), and 251 (51.0%) patients died in hospital. Of the 241 survivors, 61 (25.3%) required RRT at hospital discharge. Further patient characteristics are given in Table 1. Intradialytic hypotension was common, occurring in 428 (87.3%) of patients on one or more occasions. The median (Q1, Q3) of mean daily fluid balances over the first seven days of RRT in the entire cohort was 708 (−69, 1805) mL, with a positive mean fluid balance in 353 (71.7%) of patients. Mean daily fluid balance differed between hospital decedents (1134 (242, 2556) mL) and survivors (413 (−371, 1106) mL; P <0.01), but not between survivors who were RRT dependent at hospital discharge (71 (−330, 898) mL) and those who were not (475 (−400, 1310) mL; P = 0.36). Figures 2 and 3 show daily fluid balance over time in hospital decedents vs. survivors and in survivors requiring RRT vs. free of RRT at hospital discharge, respectively.

In this large and heterogeneous cohort of critically ill patients with AKI who received RRT, a more positive mean daily fluid balance and intradialytic hypotension in the week after RRT initiation were independently associated with an increased risk of hospital mortality, but not RRT dependence at hospital discharge in survivors. Fluid overload at commencement of RRT was associated with mortality in this cohort, as in previous studies [4],[8]-[10]. However, our main focus was on mean daily fluid balance in the week after RRT initiation, taking into account the risk of intradialytic hypotension with fluid removal, which we believed to be a clinically relevant variable with important therapeutic implications. The initiation of RRT brings with it the opportunity for clinicians to proactively and rigorously control fluid balance with relative ease, and thus the influence of fluid management on clinical outcomes has important implications for both the timing and goals of RRT.

Biological mechanisms have been proposed linking fluid overload to disruption of the endothelial glycocalyx, interstitial edema, multiple organ damage, and death [20],[21]. Limited support for the injurious effects of fluid overload on renal and other organ function comes from secondary analyses of two large randomised trials. One study found a negative mean daily fluid balance to be associated with lower 90-day mortality and increased RRT-free days in a large trial of high- vs. low-dose RRT for AKI [4], and another found a lower incidence of AKI in patients with acute respiratory distress syndrome randomized to a restrictive vs. liberal fluid management group, after correction for the dilutional effect of a positive fluid balance [22]. These associations between less fluid accumulation and improved outcomes suggest that clinicians may consider ultrafiltration to minimise or remove accumulated fluid once patients commence RRT.

We hypothesised that limiting or removing fluid overload after patients commenced RRT for AKI may ameliorate AKI severity and improve renal recovery in survivors. Although we found that a more positive fluid balance on RRT was associated with mortality, there was no association with RRT dependence at hospital discharge. Unsurprisingly, we found that intradialytic hypotension was associated with mortality. However, despite evidence that relative hypotension is associated with AKI onset in a non-critically ill hospital population [23], we found no association between intradialytic hypotension and RRT dependence. Although this finding may arise from lack of statistical power, another possible interpretation is that mild hypotension in the course of fluid removal may not reduce the probability of renal recovery in patients who survive.

Our study adds to current understanding of the relationship between fluid balance and outcomes. While previous studies have demonstrated an association between fluid overload at selected time points and death, ours is only the second study after that of Bellomo et al. [4] to demonstrate the relationship between positive fluid balance on RRT and mortality in critically ill adults, and suggests that fluid management during RRT is an important target for future clinical trials. Our sensitivity analysis adjusting for fluid accumulation at RRT initiation suggests that this relationship is not confined to those with measured fluid overload. Our cohort comprises a heterogeneous and unselected sample of critically ill patients for whom clinicians made the decision to start RRT, and demonstrates the safety of a less positive fluid management strategy.

The main limitation of this and previous similar studies is that risk adjustment cannot eliminate the possibility of residual confounding. While we adjusted for confounders such as severity of physiological derangement (SOFA score), premorbid health (Charlson comorbidity index), cardiovascular instability (use of vasopressors and intradialytic hypotension), and age, we lacked data on fluid overload at the time of RRT initiation in 40% of the cohort and therefore could not adjust for this covariate without a substantial loss of statistical power. However, sensitivity analysis in patients in whom fluid overload was calculable produced similar results to that in the whole cohort. It is also possible that other unknown confounders influenced both fluid requirements and the outcomes of mortality and RRT dependence in survivors. Immortal time bias was also a potential problem; however, a sensitivity analysis that accounted for the number of days with data available did not materially alter our findings. Residual confounding may have contributed to the surprising findings that higher baseline creatinine was associated with lower risk of death, but not with RRT dependence at discharge. These associations may reflect the occurrence of RRT-dependent AKI with less severe systemic illness among patients with pre-existing chronic kidney disease.

Other important limitations relating to the observational nature of this study include the lack of standardised criteria for the initiation of and management of RRT, leading to fluid overload as the primary indication for RRT in some patients, the lack of data on the relative contribution of intake and output to overall fluid balance, and missing data. Other limitations of data restricted the calculation of fluid balance to the first seven days following RRT initiation. Although the endpoints of mortality and RRT dependence at hospital discharge are clinically important, some patients may have been transferred to other acute care hospitals, with less certainly regarding final disposition. We defined intradialytic hypotension to include both absolute and relative hypotension and considered the frequency as a percentage of the total number of RRT sessions during which it occurred. However, similar to other AKI studies that reported details of hypotension [23], we lacked data on the duration of each episode and the frequency within individual RRT sessions. Finally, our study included data from only two hospitals, limiting applicability to other centres.

In summary, our study provides supportive evidence for reduced mortality with a less positive fluid balance after critically ill patients commence RRT. A less positive fluid management strategy does not appear to influence RRT dependence at hospital discharge. Further multicentre cohort investigations, if confirming these findings, would support the design of a randomized trial of an aggressive vs. less aggressive approach to fluid removal in this population.

A more positive fluid balance and intradialytic hypotension are associated with increased risk of death in a cohort of critically ill patients undergoing renal replacement therapy

Fluid balance and intradialytic hypotension are not associated with requirement for renal replacement therapy at the time of hospital discharge

Clinicians may consider using ultrafiltration to minimise fluid overload in critically ill patients with acute kidney injury receiving renal replacement therapy