NATURE REVIEWS | NEPHROLOGY VOLUME 7 | JUNE 2011 | 305

NEWS & VIEWSACUTE KIDNEY INJURY

Fluid therapy in acute kidney injury: the FACTTsNeil J. Glassford and Rinaldo Bellomo

The consequences of fluid administration and the maintenance of fluid balance, despite their ubiquity in critical care, remain a topic of much debate among clinicians. Emerging evidence suggests that fluid administration and a positive fluid balance can be harmful in a number of conditions, including acute kidney injury.Glassford, N. J. & Bellomo, R. Nat. Rev. Nephrol. 7, 305–306 (2011); doi:10.1038/nrneph.2011.57

The Fluid and Catheter Treatment Trial (FACTT) is the largest study to date to compare the effect of liberal and restric­tive fluid administration strategies in the critically ill patient with acute lung injury.1 This trial provided detailed data on fluid balance, dosing and duration of diuretic use for 1,000 patients, although it provided no information on type of fluid output and no hourly data. The information from FACTT, however, provides unique opportuni ties for post hoc exploratory analyses. In keeping with such opportunities, Grams et al.2 recently used these data to perform a post hoc analysis of the relationship between fluid balance, diuretic use and outcome in patients included in FACTT who developed acute kidney injury (AKI) as defined by the Acute Kidney Injury Network (AKIN) cri­teria.3 The results of their investigation suggest that, contrary to current established dogma, a positive fluid balance after the develop­ment of AKI is associated with increased mortality, as well as progression to more severe grades of AKI and increased require­ment for renal support. In addition, the data suggest that diuretics are, at least, safe to use during critical illness and may have a bene­ficial survival effect through the achievement of a more­negative fluid balance.2

AKI is common in the hospitalized patient, particularly among those requiring critical care intervention or management. Up to two­thirds of patients admitted to the intensive care unit will be suffering from some degree of AKI.4 Despite such a high incidence, very little good quality evidence exists upon which to base clini­cal guidelines for the management of this potentially lethal syndrome. The standard approach is to ensure volume repletion through the administration of intravenous fluids in the belief that intravenous fluid

loading increases diuresis, flushes partially obstructed tubules, dilutes tubular toxins, improves glomerular filtration rate (GFR) and avoids intravascular volume deple­tion.5 Although this approach has been standard practice for decades it is not clear which fluids should be used, what quantity of fluids should be used, what the end point should be or at which stage in the evolution of this condition fluids are helpful, if indeed they are helpful at all. Nonetheless, their use remains common because of concerns that alternatives such as diuretics are potentially injurious and because of the continued belief that in situations like septic AKI,6 ischemia is the cause of loss of GFR. This belief is not sustained by experimental data.7

The fluid­loading approach is based on a decades­old conceptual paradigm that AKI is a result of renal hypoperfusion from hypo­volemia. This hypovolemia leads to a fall in GFR, with a spectrum of outcomes ranging from prerenal azotemia (a protective, revers­ible volume conservation strategy), to acute tubular necrosis (a state of more advanced renal injury characterized by abnormal renal histology and cell necrosis). The administra­tion of fluids should theoreti cally increase circulating volume, renal perfusion, and GFR and hence protect both kidney and patient.5 It is now clear, however, that AKI is a much more complex condition than previously appreciated, with multiple humoral, neuro­endocrine, and inflammatory, micro­circulatory and organ cross­talk­related mechanisms involved in its pathogenesis.5 Emerging investigation into renal bio­markers further indicates that there are likely

to be heterogeneous states—character ized by different biomarker profiles—in addi­tion to the loss of renal excretory function. In this complex setting, the role of intra­venous fluid loading becomes open to chal­lenge as being futile and perhaps danger ous. Indeed, several recent studies have begun to suggest that, in the setting of AKI, a posi­tive fluid balance may be independently associated with an increased risk of death.8,9 This context is the one in which the recent publication by Grams and colleagues should be appreciated.2

From the 1,000 participants in FACTT, Grams et al. identified 306 patients meeting AKIN criteria for stage 1 AKI. Mortality at 60 days was higher in patients in the liberal fluid management arm than in patients in the fluid­conservative arm of the study (40.9% versus 37.9%) and more patients in the liberal arm required dialysis (32.1% versus 26.6%), although these differences failed to reach significance. However, when the outcome groups were analyzed further, nonsurvivors at 60 days were more likely to have had stage 2 or 3 AKI, a signifi cantly higher central venous pressure (13.3 mmHg versus 11.2 mmHg), a significantly higher rate of early oliguria, defined as a fluid output of <500 ml/24 h (50.8% versus 28.5%), and required earlier initiation of renal replace­ment therapy (42.5% versus 20.4% required dialysis within the first 7 days) than did survivors. More importantly, although there was no difference in fluid balance at base­line, a significant differ ence in average daily fluid balance developed between the two groups (3.3 l per day in nonsurvivors versus 0.3 l per day in survivors). The mean daily dose of furosemide administered was also different—25.6 mg in nonsurvivors com­pared with 73.5 mg in survivors at 60 days. However, nonsurvivors also had significantly

‘‘...we need to ensure that we first do no harm’’

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higher baseline APACHE III scores (116.7 versus 98), were more frequently in shock on enrollment (54.2–32.3%), spent a signifi­cantly longer time in shock (52% of the time versus 19.4% of the time), were signifi­cantly older (53.9 years versus 47.4 years) and had signifi cantly higher baseline urea nitrogen levels (12.4 mmol/l versus 9.3 mmol/l [34.8 mg/dl versus 26 mg/dl]) than did survivors.

A complex multiple logistic regression model that adjusted for multiple co­variants including age, race, fluid­administration strategy, APACHE III score, the pres­ence of shock and mean central venous pressure was developed. Fluid balance—through multiple sensitivity analyses and across gender, fluid strategy, early and late olig uria and severity of AKI groups—was consistently and signifi cantly associated with an increased risk of mortality, with an odds ratio for death of 1.61 per l (95% CI 1.32 to 1.96 per l) of mean positive fluid balance per day after the development of AKI. The results for furosemide dose showed a signifi cant reduction in mortality with increased dose, with an odds ratio of 0.48 (95% CI 0.28–0.81) per mean 100 mg increase in furosemide administered per day (Figure 1). Following adjustment for fluid balance, however, this apparent protective effect of furosemide disappeared.

There are limitations to the conclusions we can draw from this work. Unfortunately, only the most insensitive markers of renal function were monitored in this study. Baseline creatinine level was determined during a time when AKI was becom­ing established. In addition, the lack of

hourly data regarding fluid excretion and administra tion limits the information regarding the natural history of AKI and the relationship between oliguria and renal dysfunction and outcome. Obviously this study was a post hoc analysis of a subgroup of a study that was looking at a completely different phenomenon and so the validity of the findings may be questionable. The increased mortality may be purely reflec­tive of the illness of the patients and the treatments they subsequently received. The apparent protective effect of furosemide may be directly related to diuresis and fluid balance. Nonetheless, seen in the context of recent observations, this study raises yet more concerns that a positive fluid balance in patients with AKI is undesirable and should be actively prevented.

Importantly, the findings from Grams et al.’s paper imply that the role of fluid therapy in patients with AKI needs to be closely examined and reassessed and that formal investigations into the poten­tially beneficial effects of furosemide on fluid balance are required. Large observa­tional studies taking advantage of modern informa tion technology infrastructure seem a desirable first step. If these studies demon­strate similar findings to those of Grams et al., then trials of intervention are required, perhaps with similar designs to the FACTT study. In addition, relevant, random ized, double­blind, placebo­controlled trials of early furosemide therapy in patients with early AKI are a priority. One such study, the SPARK study, is underway.10

Given the high mortality rate associ­ated with AKI in the intensive care unit,

the human and financial impact of delayed or failed renal recovery, and the cost and complexity of renal replacement therapy, we need to ensure that we first do no harm. Avoiding a positive fluid balance may be an important first step in the right direction. This paradigm shift from ‘wet’ to ‘dry’ in patients with AKI may deliver more patient protection than any of the many interven­tions tested in patients with AKI over the last 50 years. When it comes to fluid balance in AKI, it is time to abandon untested dogma and stick to the FACTTs.

Department of Intensive Care, Austin Hospital, 147 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia (N. J. Glassford). Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, 89 Commercial Road, Melbourne, VIC 3004, Australia (R. Bellomo). Correspondence to: R. Bellomo rinaldo.bellomo@austin.org.au

Competing interestsThe authors declare no competing interests.

1. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N. Engl. J. Med. 354, 2564–2575 (2006).

2. Grams, M. E., Estrella, M. M., Coresh, J., Brower, R. G. & Liu, K. D. for the National Heart, Lung, Blood Institute Acute Respiratory Distress Syndrome Network. Fluid balance, diuretic use, and mortality in acute kidney injury. Clin. J. Am. Soc. Nephrol. doi:10.2215/CJN.08781010.

3. Mehta, R. L. et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit. Care 11, R31 (2007).

4. Hoste, E. A. & Schurgers, M. Epidemiology of acute kidney injury: how big is the problem? Crit. Care Med. 36, S146–S151 (2008).

5. Prowle, J. R., Echeverri, J. E., Ligabo, E. V., Ronco, C. & Bellomo, R. Fluid balance and acute kidney injury. Nat. Rev. Nephrol. 6, 107–115 (2010).

6. May, C. et al. A technique for the simultaneous measurement of renal ATP, blood flow and pH in a large animal model of septic shock. Crit. Care Resusc. 9, 30–33 (2007).

7. Bagshaw, S. M., Delaney, A., Haase, M., Ghali, W. A. & Bellomo, R. Loop diuretics in the management of acute renal failure: a systematic review and meta-analysis. Crit. Care Resusc. 9, 60–68 (2007).

8. Payen, D. et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit. Care 12, R74 (2008).

9. Bouchard, J. et al. Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. Kidney Int. 76, 422–427 (2009).

10. Bagshaw, S. M., Gibney, R. T., McAlister, F. A. & Bellomo, R. The SPARK Study: a phase II randomized blinded controlled trial of the effect of furosemide in critically ill patients with early acute kidney injury. Trials 11, 50 (2010).

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Figure 1 | Comparison of mean daily furosemide dose and fluid balance between survivors and nonsurvivors in Grams et al.’s study. a | Difference in mean daily furosemide dose between survivors and nonsurvivors. b | Difference in mean daily fluid balance between survivors and nonsurvivors. Data taken from Grams, M. E. et al. Clin. J. Am. Soc. Nephrol. doi:10.2215/CJN.08781010.

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