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Fluid Management and Use of Diuretics in Acute Kidney Injury

  • Annie-Claire Nadeau-Fredette
    Affiliations
    Division of Nephrology, Department of Medicine, Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montréal, Canada
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  • Josée Bouchard
    Correspondence
    Address correspondence to Josée Bouchard, MD, FRCPC, Research Center, Hôpital du Sacré-Cœur de Montréal, 5400 Blvd. Gouin west, Montréal, Quebec H4J 1C5, Canada.
    Affiliations
    Division of Nephrology, Department of Medicine, Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montréal, Canada
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      Critically ill adult patients at risk for or with acute kidney injury (AKI) require careful attention to their hemodynamic status because hypotension and hypovolemia may contribute to or worsen kidney injury. Increasing evidence suggests that isotonic crystalloids should be used instead of colloids for initial expansion of intravascular volume in patients at risk for AKI or with AKI, such as those with sepsis, septic shock, or trauma. The timing and amount of volume to be administered to prevent AKI and other organ damage is still debated, but an aggressive fluid repletion in the early setting is probably beneficial. However, fluid overload has also been associated with increased mortality and reduced rate of kidney recovery in observational studies in critically ill patients with AKI. Diuretics may prevent or treat fluid overload and may also affect kidney function. The efficacy of these procedures in critically ill AKI patients need to be confirmed with randomized controlled trials. This review focuses on early volume resuscitation, overall fluid management, and use of diuretics in critically ill adult patients at risk for or with AKI and their effect on mortality and kidney function in this setting.

      Key Words

      • There is increasing evidence suggesting that isotonic crystalloids should be used instead of colloids as initial management for expansion of intravascular volume in critically ill adult patients at risk for AKI or with AKI, such as those with sepsis, septic shock, or trauma.
      • The optimal timing and amount of initial volume resuscitation to prevent AKI, to reduce its severity, and to improve mortality in these clinical settings still needs to be defined, although a more aggressive early fluid repletion is probably beneficial.
      • Once AKI occurs and that hemodynamic status is stabilized, the relevance of restrictive fluid management and the use of diuretics or renal replacement therapy to prevent or treat fluid overload and improve outcomes in this population, without worsening kidney function, needs to be confirmed with randomized controlled trials.

      Introduction

      Acute kidney injury (AKI) is a frequent condition encountered in hospitalized patients, especially in critically ill adult patients in which its incidence can reach 65%.
      • Bagshaw S.M.
      • George C.
      • Bellomo R.
      • Committe A.D.M.
      A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients.
      • Singbartl K.
      • Kellum J.A.
      AKI in the ICU: Definition, epidemiology, risk stratification, and outcomes.
      • Hoste E.A.J.
      • Kellum J.A.
      Acute kidney injury: Epidemiology and diagnostic criteria.
      • Mandelbaum T.
      • Scott D.J.
      • Lee J.
      • et al.
      Outcome of critically ill patients with acute kidney injury using the Acute Kidney Injury Network criteria.
      Several studies have shown that AKI is associated with an increase in morbidity and mortality in critically ill and hospitalized patients.
      • Bagshaw S.M.
      • George C.
      • Bellomo R.
      • Committe A.D.M.
      A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients.
      • Chertow G.M.
      • Burdick E.
      • Honour M.
      • Bonventre J.V.
      • Bates D.W.
      Acute kidney injury, mortality, length of stay, and costs in hospitalized patients.
      • Barrantes F.
      • Feng Y.
      • Ivanov O.
      • et al.
      Acute kidney injury predicts outcomes of non-critically ill patients.
      However, few therapeutic interventions have been successful in treating or preventing AKI, often because of delayed diagnosis and interventions. Patients at risk for or with AKI require careful attention to their hemodynamic status because hypovolemia can decrease kidney perfusion and contribute to kidney injury. Early fluid administration aims to prevent and/or minimize the effects of AKI. However, recent observational studies in critically ill patients have suggested that fluid overload may have a negative influence on kidney function and mortality.
      • Bouchard J.
      • Soroko S.B.
      • Chertow G.M.
      • et al.
      Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.
      • Payen D.
      • de Pont A.C.
      • Sakr Y.
      • et al.
      A positive fluid balance is associated with a worse outcome in patients with acute renal failure.
      • Heung M.
      • Wolfgram D.F.
      • Kommareddi M.
      • Hu Y.
      • Song P.X.
      • Ojo A.O.
      Fluid overload at initiation of renal replacement therapy is associated with lack of renal recovery in patients with acute kidney injury.
      In this setting, volume resuscitation, fluid management, and diuretics can influence overall prognosis. In this review, “volume resuscitation” refers to the amount and types of fluids used during the initial period (ie, hours) after an acute event such as sepsis, and “fluid management” to the regulation of input and output over the intensive care unit (ICU) and subsequent hospital stay (ie, days after an acute event). We will successively review recent literature on volume resuscitation, fluid management, and use of diuretics in critically ill adult patients with AKI.

      Volume Resuscitation

      Intravenous fluid administration is frequently used in hospitalized patients. For example, this intervention is believed to prevent AKI or treat AKI in sepsis, trauma, or burns, although few studies have evaluated its effect on kidney function or mortality, except for the prevention of contrast-induced nephropathy.
      • Pannu N.
      • Wiebe N.
      • Tonelli M.
      Prophylaxis strategies for contrast-induced nephropathy.
      In severe sepsis and septic shock, since the landmark study by Rivers and colleagues, the administration of intravenous fluids and vasopressors in the first hours of an acute critical illness has been considered one of the most important interventions toward better outcomes.
      • Rivers E.
      • Nguyen B.
      • Havstad S.
      • et al.
      Early goal-directed therapy in the treatment of severe sepsis and septic shock.
      This trial on early goal-directed therapy (EGDT) performed at one emergency department randomized 130 patients for 6 hours to EGDT and 133 patients to standard therapy. EGDT included the administration of crystalloids, vasopressors, and red blood cells according to predefined parameters. The mortality was significantly lower in the EGDT group (30.5% vs 46.5%, P = 0.009). The incidence of AKI was not reported; therefore, there are no definitive data on the influence of EGDT on AKI prevention or treatment. Patients in the EGDT group had a significantly higher volume of fluid administered during the first 6 hours (4981 mL vs 3499 mL), and both groups received more than 13 L over 72 hours. Limitations of this study include its single-center design and the specific population. Three large RCTs are currently performed to reassess this therapy in the United States (Protocolized Care for Early Septic Shock [ProCESS]), United Kingdom, and Australia (Australasian Resuscitation In Sepsis Evaluation Randomised Controlled Trial [ARISE]). The ARISE study will analyze the need for renal replacement therapy (RRT) at 28 and 90 days as a secondary endpoint.
      In volume resuscitation, the optimal repletion fluid—namely isotonic crystalloids, synthetic colloids (hydroxyethylstarch [HES], gelatin, and dextran), or albumin—remains a controversial subject. Crystalloids are thought to exacerbate pulmonary and peripheral edema by increasing fluid extravasation whereas colloids tend to remain in a larger proportion in the intravascular space, reducing the amount of replacement fluid required,
      • Jacob M.
      • Chappell D.
      • Conzen P.
      • Wilkes M.M.
      • Becker B.F.
      • Rehm M.
      Small-volume resuscitation with hyperoncotic albumin: A systematic review of randomized clinical trials.
      the degree of hypoalbuminemia, and perhaps pulmonary leakiness.
      • Ertmer C.
      • Rehberg S.
      • Van Aken H.
      • Westphal M.
      Relevance of non-albumin colloids in intensive care medicine.
      However, colloids have been associated with an increased risk of complications and adverse effects on kidney function.
      • Perel P.
      • Roberts I.
      Colloids versus crystalloids for fluid resuscitation in critically ill patients.
      Recently, the Kidney Disease Improving Global Outcome (KDIGO) Clinical Practice Guidelines for AKI have suggested that isotonic crystalloids should be used ahead of synthetic and nonsynthetic colloids for intracellular volume expansion in patients at risk or presenting with AKI, in the absence of hemorrhagic shock.
      KDIGO AKI Guideline.
      This recommendation was based on the adverse effects of synthetic colloids, most commonly HES, over isotonic crystalloids on mortality and other outcomes, including AKI and need for RRT. In 2011, the Cochrane Collaboration group systematically reviewed 56 randomized controlled trials (RCTs) and concluded that colloids are not superior to isotonic crystalloids in terms of mortality when used for intravascular volume repletion in patients with trauma, burns, or after surgery.
      • Perel P.
      • Roberts I.
      Colloids versus crystalloids for fluid resuscitation in critically ill patients.
      We will review the recent studies that led to these recommendations (Table 1).
      Table 1Early Volume Resuscitation: Colloids vs Crystalloids Solutions
      Authors, YearStudy TypeNumber (n) and Characteristics of PatientsNumber and Characteristics of Patients in SubgroupsAKI DefinitionOutcomeComments
      Sark, 2007
      • Sakr Y.
      • Payen D.
      • Reinhart K.
      • et al.
      Effects of hydroxyethyl starch administration on renal function in critically ill patients.
      Retrospective (data collected prospectively)n = 3147, ICUn = 1075, HES (type not specified)

      n = 2072, non-HES
      Non-HES group including crystalloids, albumin, and gelatins.
      RRT requirementKidney function: No increased risk for RRT with HESHES group with more comorbidities and increased mortality
      Schorten, 2008
      • Schortgen F.
      • Girou E.
      • Deye N.
      • Brochard L.
      • Group C.S.
      The risk associated with hyperoncotic colloids in patients with shock.
      Prospective cohortn = 822, shockn = 127, crystalloids only

      n = 189, hypooncotic colloids
      Hypooncotic colloids: 4% albumin (8% of patients) or gelatins (97% of patients).


      n = 401, artificial hyperoncotic colloids
      Artificial hyperoncotic colloids: HES (98% of patients, both modern—130 kDa/0.4—and older starch) or dextran (3% of patients).


      n = 105, hyperoncotic albumin (20-25%)
      Doubling of creatinine or RRT requirementKidney function: Increased risk for AKI with artificial hyperoncotic colloids OR 2.13 (1.08-4.20) and hyperoncotic albumin OR 5.27 (2.44-11.37)Volumes of solutions not reported
      Brunkhorst, 2008
      • Brunkhorst F.M.
      • Engel C.
      • Bloos F.
      • et al.
      Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
      RCTn = 537, severe sepsisn = 262, pentastarch,

      n = 275, Ringer's lactate
      Doubling of creatinine or RRT requirementKidney function: Increased risk for AKI with pentastarch (34.9% vs 22.8%, P = 0.002)

      Mortality: Increased 90-d mortality with pentastarch dose >22 mL/kg
      Dose-effect relation with mortality and RRT
      Ertmer, 2008

      Ertmer C, Pintol B, Rehberg S. Incidence of renal replacement therapy in intensive care patients treated with different hydroxyethyl starch solutions. Poster 0764 presented at:21st ESICM Annual Congress, Lisbon, Portugal, September 21–24, 2008.

      Retrospectiven = 8408, ICUn = 595, 10% HES 200/0.5

      n = 7813, 6% HES 130/0.4,
      RRT requirementKidney function: Higher risk of RRT with 10% HES 200/0.5 compared with 6% HES 130/0.4 (35.5% vs 6.1%; OR 11.5; [9.5-14.1])Abstract only
      Hypooncotic colloids: 4% albumin (8% of patients) or gelatins (97% of patients).
      Rioux, 2009
      • Rioux J.P.
      • Lessard M.
      • De Bortoli B.
      • et al.
      Pentastarch 10% (250 kDa/0.45) is an independent risk factor of acute kidney injury following cardiac surgery.
      Retrospectiven = 563, cardiac surgeryn = 54, with AKI, mean dose of pentastarch 16 ± 9 mL/kg

      n = 509, no AKI, mean dose of pentastarch 10 ± 7 mL/kg
      50% rise in serum creatinine within 4 d after surgeryKidney function: Pentastarch associated with an increased risk of AKI, adjusted OR per mL/kg of 1.08 (1.04 -1.12)Optimal cutoff volume to predict AKI = 14 mL/kg
      Boussekey, 2010
      • Boussekey N.
      • Darmon R.
      • Langlois J.
      • et al.
      Resuscitation with low volume hydroxyethylstarch 130 kDa/0.4 is not associated with acute kidney injury.


      Perner, 2012
      • Perner A.
      • Haase N.
      • Guttormsen A.B.
      • et al.
      Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.
      Retrospective

      Blinded RCT
      n = 363, ICU > 72 h

      n = 804, critically ill patients with severe sepsis (798 included in the modified intention-to-treat analysis)
      n = 168, HES (130 kDa/0.4),

      n = 195, non-HES

      n = 398, HES (130 kDa/0.4), n = 400, Ringer's acetate up to 33 mL/kg ideal body weight/d
      RIFLE injury or failure

      Use of RRT or kidney SOFA score of ≥3 after the patient had a score of ≤2, doubling of serum creatinine in the ICU
      Kidney function: No increased risk for AKI with HES

      Kidney function: Higher need for RRT in the 90-d period in patients treated with HES (22% vs 16%; RR 1.35 [1.01-1.80] but no increased risk for RRT at day 90, no difference in AKI

      Mortality: higher mortality at day 90 in patients treated with HES (51% vs 43%; RR 1.17 [1.01-1.36]
      Low-dose HES, 763 ± 593 mL during first 48 h

      Similar results were found in the 282 patients with AKI at baseline, defined by a kidney SOFA score of ≥2 (>1.9 mg/dL or urinary output <500 mL/d)
      SAFE study, 2004
      • Finfer S.
      • Bellomo R.
      • Boyce N.
      • et al.
      A comparison of albumin and saline for fluid resuscitation in the intensive care unit.
      RCTn = 6997, ICUn = 3497, albumin 4%,

      n = 3500, normal saline
      Duration of RRTKidney function: no difference in duration of RRT

      Mortality: No difference in 28-d mortality
      SAFE substudy traumatic brain injury, 2007
      • Investigators SS, Group AaNZICSCT, Service ARCB
      • et al.
      Saline or albumin for fluid resuscitation in patients with traumatic brain injury.
      Post hoc analysis from SAFE studyn = 406, ICU with traumatic brain injuryn = 255, albumin 4%

      n = 260, saline
      Not definedMortality: Higher mortality at 24 mo in patients treated with albumin (OR 1.63 [1.17-2.26])Majority of deaths during the first 28 d in both groups
      SAFE substudy, severe sepsis, 2011
      • Investigators SS
      • Finfer S.
      • McEvoy S.
      • et al.
      Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis.
      Post hoc analysis from SAFE studyn = 1218, ICU with severe sepsisn = 603, albumin 4%

      n = 615, saline
      SOFA score and RRT requirementKidney function: no difference

      Mortality: lower risk of death with albumin OR = 0.7 (0.52-0.97)
      Abbreviation: RIFLE, Risk, Injury, Failure, Loss, End-Stage Renal Disease.
      Non-HES group including crystalloids, albumin, and gelatins.
      Hypooncotic colloids: 4% albumin (8% of patients) or gelatins (97% of patients).
      Artificial hyperoncotic colloids: HES (98% of patients, both modern—130 kDa/0.4—and older starch) or dextran (3% of patients).

      Synthetic Colloids

      Different HES preparations exist, and they vary according to their concentration, mean molecular weight, molar substitution, and substitution of hydroxyethyl for hydroxyl groups. The colloid osmotic pressure effect mainly depends on the concentration of colloid in the solution. For example, 6% HES is iso-oncotic and 10% HES is hyperoncotic. The side effects may also vary according to the type of HES.
      Studies on HES have looked at their adverse effects on kidney function, need for RRT, and/or mortality in critically ill patients (Table 1). Only one large study concluded that HES seemed safe with regards to kidney function based on kidney SOFA score and RRT requirement.
      • Sakr Y.
      • Payen D.
      • Reinhart K.
      • et al.
      Effects of hydroxyethyl starch administration on renal function in critically ill patients.
      In this retrospective study, 34% of patients received HES (type unspecified), 41% received crystalloids, and 25% received a combination of crystalloids and non-HES colloids (gelatin, dextran, or 5% and 20% albumin). The retrospective nature of the study, the low volume of HES used (total amount 1000 mL in an average of 2 day period), and the absence of data on the specific type of HES used represent major limitations to support the conclusion of the study.
      Three large studies have concluded that hyperoncotic colloids increase AKI risk.
      • Brunkhorst F.M.
      • Engel C.
      • Bloos F.
      • et al.
      Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
      • Schortgen F.
      • Girou E.
      • Deye N.
      • Brochard L.
      • Group C.S.
      The risk associated with hyperoncotic colloids in patients with shock.
      • Rioux J.P.
      • Lessard M.
      • De Bortoli B.
      • et al.
      Pentastarch 10% (250 kDa/0.45) is an independent risk factor of acute kidney injury following cardiac surgery.
      The VISEP RCT, a factorialized study of starch and insulin, compared 10% pentastarch (HES 200 kDa/0.5) and Ringer's lactate in severe sepsis.
      • Brunkhorst F.M.
      • Engel C.
      • Bloos F.
      • et al.
      Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
      This trial was stopped for safety reasons in the insulin treatment arm. The interim analysis showed a significant higher incidence of AKI (34.9% vs 22.8%, P = 0.002) and RRT (31.0% vs 18.8%, P = 0.001) and a trend toward increased mortality at 90 days in the HES group. It is interesting to note that this study suggested a dose-response relationship between colloid administration and mortality. The 90-day mortality was 57.6% with a pentastarch dose greater than 22 mL/kg and 30.9% in the lower dose group (P < 0.001). This relationship was not present in patients in the Ringer's lactate group, who received a higher amount of fluids. Unfortunately, the results of this study are confounded by the high doses of HES administered (median cumulative dose of 70 mL/kg), which were higher than the maximal recommended doses in more than 30% of patients. In a prospective cohort study, Schortgen and colleagues looked at the effect of synthetic colloids, albumin, and crystalloids on kidney function in patients with shock.
      • Schortgen F.
      • Girou E.
      • Deye N.
      • Brochard L.
      • Group C.S.
      The risk associated with hyperoncotic colloids in patients with shock.
      After multivariate adjustment, hyperoncotic colloids (odds ratio [OR] 2.13; 95% confidence interval [CI] 1.08-4.20) and hyperoncotic albumin (OR 5.27; 95% CI 2.44-11.37) were associated with an increased risk of AKI. Hyperoncotic albumin was also associated with an increased risk of death. The median cumulative HES dose was 31 mL/kg, but the amount of fluid volume administered and the fluid balance were not reported, which are potential confounders. Finally, a retrospective study evaluated the risk of AKI using lower doses of pentastarch 10% in patients undergoing cardiac surgery.
      • Rioux J.P.
      • Lessard M.
      • De Bortoli B.
      • et al.
      Pentastarch 10% (250 kDa/0.45) is an independent risk factor of acute kidney injury following cardiac surgery.
      The risk was dependent on dose (OR per mL/kg 1.08; 95% CI 1.04-1.12), and the optimal cutoff volume predicting AKI was only 14 mL/kg.
      Low-molecular-weight HES have also been recently associated with adverse outcomes in critically ill patients.
      • Perner A.
      • Haase N.
      • Guttormsen A.B.
      • et al.
      Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.
      A large RCT in patients with severe sepsis showed that 6% HES 130/0.42 increased mortality and the RRT requirement compared with Ringer's acetate (relative risk [RR] 1.17; 95% CI 1.01-1.36 and RR 1.35; 95% CI 1.01-1.80, respectively). There were no differences in terms of dialysis dependence or AKI incidence at 90 days. This study was the only one to predefine an AKI subgroup, and this subgroup also presented an increased mortality and RRT requirement with 6% HES. A retrospective study comparing the effect of 6% HES 130/0.4 and 10% HES 200/0.5 on the RRT requirement in 8408 critically ill patients showed that the need for RRT was lower in patients treated with 6% than with 10% HES (6.1% vs 35.5%; OR 11.5; 95% CI 9.5-14.1).

      Ertmer C, Pintol B, Rehberg S. Incidence of renal replacement therapy in intensive care patients treated with different hydroxyethyl starch solutions. Poster 0764 presented at:21st ESICM Annual Congress, Lisbon, Portugal, September 21–24, 2008.

      In addition, mean creatinine levels were lower in the 6% compared with the 10% HES group. However, with respect to the results from the recent large RCT completed by Perner and colleagues,
      • Perner A.
      • Haase N.
      • Guttormsen A.B.
      • et al.
      Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis.
      low-molecular-weight synthetic colloids seem to have an harmful effect on mortality and kidney function and should be avoided.

      Albumin

      The SAFE study randomized 7000 ICU patients to either 4% albumin or normal saline for intravascular fluid resuscitation and found no differences in 28-day mortality or in new organ dysfunction, duration of RRT, and other secondary endpoints (Table 1).
      • Finfer S.
      • Bellomo R.
      • Boyce N.
      • et al.
      A comparison of albumin and saline for fluid resuscitation in the intensive care unit.
      Kidney function was not independently reported. As expected, patients in the saline group had a higher positive fluid balance during the first 3 days. However a low proportion of patients received large volume fluid resuscitation (>5 L) and thus the results may not be applicable to all patients. Two subgroup analyses were subsequently published. In the traumatic brain injury subgroup, which included 460 patients, patients who received albumin had an increased mortality at 24 months (33.2% vs 20.4%, P = 0.003).
      • Investigators SS, Group AaNZICSCT, Service ARCB
      • et al.
      Saline or albumin for fluid resuscitation in patients with traumatic brain injury.
      In contrast, the substudy with severe sepsis showed a lower risk of death in patients treated with albumin (OR = 0.71; 95% CI 0.52-0.97).
      • Investigators SS
      • Finfer S.
      • McEvoy S.
      • et al.
      Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis.
      The kidney Sequential Organ Failure Assessment (SOFA) scores and the incidence of RRT were not different between groups. On the basis of these three studies, 4% albumin should be avoided in patients with traumatic brain injury but could be considered in other patients, especially those with severe sepsis, without major concerns about kidney function. Other risks associated with albumin administration, such as transmission of virus and theoretically, the Creutzfeldt-Jakob disease agent, need to be taken into account in this decision process.
      Hyperoncotic albumin was evaluated in a meta-analysis that included 7 RCTs in critically ill and noncritically patients.
      • Wiedermann C.J.
      • Dunzendorfer S.
      • Gaioni L.U.
      • Zaraca F.
      • Joannidis M.
      Hyperoncotic colloids and acute kidney injury: A meta-analysis of randomized trials.
      Albumin at 20-25% was shown to have a protective effect on kidney function (OR 0.24; 95% CI 0.12-0.48) and mortality (OR 0.52; 95% CI 0.28-0.95), as opposed to the results by Schortgen and colleagues previously reported. A major limitation of this meta-analysis is the inclusion of a significant proportion of patients with cirrhosis (6 of 7 studies). This specific population might benefit more from albumin repletion.
      In summary, we do agree with the KDIGO and Cochrane group recommendations and favor the use of isotonic crystalloids over colloids in patients at risk or with AKI. Synthetic colloid solutions should be avoided because of their negative effect on kidney function and survival. Hypooncotic albumin could be used in patients with sepsis bearing in mind their infectious risk and should be avoided in traumatic brain injury. Hypooncotic albumin may also have a role in patients requiring large amounts of fluid, and hyperoncotic albumin should probably be avoided except for cirrhotic patients. Recent studies suggested that the type of crystalloid solution used may also influence outcomes. An observational study showed that a calcium-free balanced crystalloid solution on the day of major surgery was associated with fewer complications than 0.9% saline, including infections and AKI requiring RRT.
      • Shaw A.D.
      • Bagshaw S.M.
      • Goldstein S.L.
      • et al.
      Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte.
      Future studies on volume resuscitation should assess the role of balanced crystalloid solutions compared with isotonic saline.

      Late Fluid Management

      Over the last years, a few RCTs and several observational studies have shown that excessive fluid repletion leading to fluid overload may have a negative influence on survival, cardiopulmonary complications, kidney function, and wound healing in critically ill adult patients (Table 2).
      • Bouchard J.
      • Soroko S.B.
      • Chertow G.M.
      • et al.
      Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.
      • Payen D.
      • de Pont A.C.
      • Sakr Y.
      • et al.
      A positive fluid balance is associated with a worse outcome in patients with acute renal failure.
      • Heung M.
      • Wolfgram D.F.
      • Kommareddi M.
      • Hu Y.
      • Song P.X.
      • Ojo A.O.
      Fluid overload at initiation of renal replacement therapy is associated with lack of renal recovery in patients with acute kidney injury.
      • National Heart Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network
      • Wiedemann H.P.
      • Wheeler A.P.
      • et al.
      Comparison of two fluid-management strategies in acute lung injury.
      • Vincent J.L.
      • Sakr Y.
      • Sprung C.L.
      • et al.
      Sepsis in European intensive care units: Results of the SOAP study.
      • Murphy C.V.
      • Schramm G.E.
      • Doherty J.A.
      • et al.
      The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock.
      • Upadya A.
      • Tilluckdharry L.
      • Muralidharan V.
      • Amoateng-Adjepong Y.
      • Manthous C.A.
      Fluid balance and weaning outcomes.
      • Brandstrup B.
      • Tonnesen H.
      • Beier-Holgersen R.
      • et al.
      Effects of intravenous fluid restriction on postoperative complications: Comparison of two perioperative fluid regimens: A randomized assessor-blinded multicenter trial.
      • RENAL Replacement Therapy Study Investigators
      • Bellomo R.
      • Cass A.
      • et al.
      An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs. Augmented Level of Renal Replacement Therapy trial.
      These studies have not looked at the specific type of fluid administered (namely crystalloids or colloids), which represents a significant limitation. In AKI, once hemodynamic status is stabilized, we usually aim for a neutral or restrictive fluid balance depending on the clinical context to prevent or treat significant fluid overload despite the lack of randomized data. However, the safety and efficacy of this procedure need to be confirmed with RCTs. We will first review recent data on fluid management in critical care patients to provide a broader overview of the results in the literature and then in critical care patients with AKI. We will also briefly discuss the effect of fluid management on AKI diagnosis.
      Table 2Effect of Fluid Balance in LFM
      Author, YearStudy TypePopulation Number (n) and CharacteristicsSubgroups Number (n) and CharacteristicsAssessment of Kidney FunctionOutcomes
      Upadya, 2005
      • Upadya A.
      • Tilluckdharry L.
      • Muralidharan V.
      • Amoateng-Adjepong Y.
      • Manthous C.A.
      Fluid balance and weaning outcomes.
      Prospective observationaln = 87, ICU on mechanical ventilationn = 38 with first-day weaning success,

      n = 49 patients with first-day weaning failure
      Not reportedPulmonary outcome: Increased first-day weaning success with negative cumulative fluid balance OR 3.4, (1.3-8.4) and 24 h before breathing trial OR 2.9, (1.1-7.6)
      ARDS Clinical Trial Network, 2006
      • National Heart Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network
      • Wiedemann H.P.
      • Wheeler A.P.
      • et al.
      Comparison of two fluid-management strategies in acute lung injury.
      RCTn = 1000, ALIn = 503, conservative fluid management (−136 mL)

      n = 497 liberal fluid management (+6992 mL) over 7 d
      RRT requirementMortality: no difference

      Pulmonary outcome: increased number of ventilator-free days (14.6 vs 12.1, P < 0.001);

      Kidney function: trend toward lower RRT within 60 d 10% vs 14%, P = 0.06)
      Vincent, 2006
      • Vincent J.L.
      • Sakr Y.
      • Sprung C.L.
      • et al.
      Sepsis in European intensive care units: Results of the SOAP study.
      Retrospective (data collected prospectively)n = 3147, ICUn = 1177, with sepsis (total fluid balance 0.1 ± 5.3 L),

      n = 1970, no sepsis (total fluid balance 0.4 ± 17.8 L)
      Kidney SOFA score
      Kidney SOFA score: creatinine >3.5 mg/dL or urine output 500 mL/d.
      Mortality: Increased risk of death OR 1.1 (1.0-1.1) per liter increase of cumulative balance within first 72 h in patients with sepsis
      Murphy, 2009
      • Murphy C.V.
      • Schramm G.E.
      • Doherty J.A.
      • et al.
      The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock.
      Retrospectiven = 212 septic shock and ALIn = 93, adequate IFR + conservative LFM,

      n = 31 inadequate IFR + conservative LFM,

      n = 53 adequate IFR + liberal LFM,

      n = 35 inadequate IFR + liberal LFM
      Not reportedMortality: lower mortality with adequate IFR + conservative LFM (18.3%) than other strategies (inadequate IFR + conservative LFM (56.6%), adequate IFR + liberal LFM (41.9%), inadequate IFR + liberal LFM (77.1%), P < 0.001)
      Payen, 2008
      • Payen D.
      • de Pont A.C.
      • Sakr Y.
      • et al.
      A positive fluid balance is associated with a worse outcome in patients with acute renal failure.
      Retrospectiven = 3147, ICUn = 1120 with AKI, n = 2027 without AKIKidney SOFA score
      Kidney SOFA score: creatinine >3.5 mg/dL or urine output 500 mL/d.
      Mortality: with AKI, mean fluid-balance associated with increased 60-d mortality, HR 1.21 (1.13-1.28) per liter per 24 h
      Bouchard, 2009
      • Bouchard J.
      • Soroko S.B.
      • Chertow G.M.
      • et al.
      Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.
      Retrospective (data collected prospectively)n = 542, AKI in ICUn = 243, with FO
      FO defined by percentage of fluid accumulation >10% over baseline weight at hospital admission.


      n = 299, without FO
      RRT independenceMortality: increased 60-d death with FO (46% vs 32%, P = 0.006), Multivariate analysis: FO at initiation of RRT: OR 2.07 (1.27-3.37), FO at peak creatinine (nondialyzed) OR 3.14 (1.18-8.33)

      Kidney function: no effect of FO at diagnosis on kidney recovery

      FO at peak creatinine associated with reduced kidney recovery (35% vs 52%, P < 0.001)
      Heung, 2012
      • Heung M.
      • Wolfgram D.F.
      • Kommareddi M.
      • Hu Y.
      • Song P.X.
      • Ojo A.O.
      Fluid overload at initiation of renal replacement therapy is associated with lack of renal recovery in patients with acute kidney injury.
      Retrospectiven = 170, on RRT with presumed acute tubular necrosisn = 61, kidney recovery

      n = 109, nonrecovery of kidney function
      RRT independence

      RRT independence
      Kidney function: FO at RRT initiation was a significant negative predictor of recovery of kidney function HR 0.97, (0.95-1.0) for each rise in percent
      RENAL Replacement Therapy Study Investigators, 2012
      • RENAL Replacement Therapy Study Investigators
      • Bellomo R.
      • Cass A.
      • et al.
      An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs. Augmented Level of Renal Replacement Therapy trial.
      Retrospective (data collected prospectively)n = 1453, on RRT in ICU for AKIn = 705, positive mean daily fluid balance

      n = 748, negative mean daily fluid balance
      Mortality: negative mean daily fluid balance associated with decreased mortality at 90 d OR 0.318 (0.24-0.43)

      Kidney function: negative mean daily fluid balance was associated with increased RRT-free days (P = 0.0017)
      Abbreviations: ALI, acute lung injury; FO, fluid overload.
      Kidney SOFA score: creatinine >3.5 mg/dL or urine output 500 mL/d.
      FO defined by percentage of fluid accumulation >10% over baseline weight at hospital admission.

      Fluid Management in Critically Ill Adult Patients

      The largest RCT performed on late fluid management (LFM), the Fluids and Catheters Treatment Trial (FACTT), showed a negative effect of fluid accumulation on pulmonary function but failed to show an improved survival with a conservative fluid strategy.
      • National Heart Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network
      • Wiedemann H.P.
      • Wheeler A.P.
      • et al.
      Comparison of two fluid-management strategies in acute lung injury.
      The trial was powered to assess mortality in patients with acute lung injury and compared a conservative versus a liberal strategy of fluid management over 1 week. Patients in the conservative strategy had a cumulative fluid balance of −136 mL vs +6992 mL in the liberal group. The conservative group had an increased number of ventilator-free days and a shorter length of ICU stay. There was a trend toward lower RRT requirement during the first 60 days in the conservative group (10% vs 14%, P = 0.06). A small prospective cohort of ventilated patients also showed that negative fluid balance 24 hours before breathing trial and negative cumulative fluid balance were independently associated with first-day weaning success.
      • Upadya A.
      • Tilluckdharry L.
      • Muralidharan V.
      • Amoateng-Adjepong Y.
      • Manthous C.A.
      Fluid balance and weaning outcomes.
      Diuretics were not associated with a higher weaning success, and no data were available on kidney function.
      Observational studies have shown an association between fluid balance and mortality.
      • Vincent J.L.
      • Sakr Y.
      • Sprung C.L.
      • et al.
      Sepsis in European intensive care units: Results of the SOAP study.
      • Murphy C.V.
      • Schramm G.E.
      • Doherty J.A.
      • et al.
      The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock.
      The Sepsis Occurrence in Acutely Ill Patients (SOAP) study included 3147 ICU patients, among them 1177 with sepsis.
      • Vincent J.L.
      • Sakr Y.
      • Sprung C.L.
      • et al.
      Sepsis in European intensive care units: Results of the SOAP study.
      Positive cumulative balance within the first 72 hours was associated with an increased risk of mortality in sepsis (OR per liter increase 1.1; 95% CI 1.0-1.1). A smaller retrospective study looked at the combination of adequate initial volume resuscitation and conservative LFM in 212 patients with septic shock and acute lung injury. The study categorized patients according to the initial volume resuscitation strategy used during the first 6 hours of septic shock (initial fluid resuscitation [IFR]) and the fluid strategy used from 6 hours to 7 days after shock onset (LFM).
      • Murphy C.V.
      • Schramm G.E.
      • Doherty J.A.
      • et al.
      The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock.
      IFR was “adequate” if a fluid bolus greater than 20 mL/kg was administered before vasopressor treatment initiation and if patients had a central venous pressure greater than 8 mmHg during the 6 first hours. For LFM, ”conservative” strategy was defined as even-to negative fluid balance for 2 or more consecutive days during the first week. Hospital mortality was lowest for those achieving an adequate IFR and a conservative LFM (18%), and mortality rates increased when patients did not meet late conservative goals (42%), early adequate goals (57%), or both early adequate and late conservative (77%) goals. The incidence and evolution of AKI were not mentioned. This observational study suggests taking into consideration the timing of the critical illness when making decisions on fluid administration and supports the importance of a rapid and adequate fluid repletion in the first hours of septic shock, and, if feasible, a subsequent neutral fluid balance.
      • Rivers E.
      • Nguyen B.
      • Havstad S.
      • et al.
      Early goal-directed therapy in the treatment of severe sepsis and septic shock.
      The effect of such a strategy on kidney function is unknown.

      Fluid Management in Critically Ill Adult Patients with AKI

      A few observational studies and subsequent analyses of the FACTT and Randomized Evaluation of Normal vs Augmented Level (RENAL) trials have shown an association between fluid balance and mortality in adults with AKI. The effect of fluid overload on kidney function was less consistent. The first study was a subsequent analysis of the SOAP study cited above.
      • Vincent J.L.
      • Sakr Y.
      • Sprung C.L.
      • et al.
      Sepsis in European intensive care units: Results of the SOAP study.
      Among the initial 3127 patients, 36% had AKI.
      • Payen D.
      • de Pont A.C.
      • Sakr Y.
      • et al.
      A positive fluid balance is associated with a worse outcome in patients with acute renal failure.
      Mean fluid balance was an independent risk factor for 60-day mortality (HR 1.21 [per liter per 24 hours], P < 0.001). When patients with AKI within or after 2 days after ICU admission were analyzed separately, mean fluid balance remained an independent predictor of mortality only in early AKI. There were no data available on the effect of fluid balance on kidney function. A subsequent analysis of the FACTT trial also recently showed that a positive fluid balance after AKI was strongly associated with mortality.
      • National Heart Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network
      • Wiedemann H.P.
      • Wheeler A.P.
      • et al.
      Comparison of two fluid-management strategies in acute lung injury.
      The RENAL trial randomized 1508 AKI patients on RRT to higher versus lower intensity therapy and showed that a negative mean daily fluid balance during RRT was associated with a decreased risk of death and increased RRT-free days.
      • RENAL Replacement Therapy Study Investigators
      • Bellomo R.
      • Cass A.
      • et al.
      An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs. Augmented Level of Renal Replacement Therapy trial.
      No data on fluid balance were available before RRT initiation.
      The PICARD study showed that fluid overload, defined as a percentage of fluid accumulation more than 10% over baseline weight at hospital admission, was also associated with a significantly higher mortality at 60 days and at hospital discharge.
      • Bouchard J.
      • Soroko S.B.
      • Chertow G.M.
      • et al.
      Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.
      After multivariate adjustment, the OR for death associated with fluid overload at dialysis initiation was 2.07 (95% CI 1.27-3.37) and was 3.14 (95% CI 1.18-8.33) for nondialyzed patients at AKI diagnosis. The study also showed an increase in the risk of death proportional to the magnitude and duration of fluid accumulation. The effect of fluid overload on kidney recovery was inconsistent. Fluid overload at the time of AKI diagnosis was not associated with recovery of kidney function; however, patients with fluid overload at their peak serum creatinine were significantly less likely to recover kidney function. There was no relationship between the degree of fluid overload at dialysis initiation and subsequent dialysis independence.
      A retrospective smaller study showed that dialyzed patients who subsequently became dialysis-independent had significantly less fluid overload at the time of RRT initiation (3.5% vs 9.3%, P = 0.004).
      • Heung M.
      • Wolfgram D.F.
      • Kommareddi M.
      • Hu Y.
      • Song P.X.
      • Ojo A.O.
      Fluid overload at initiation of renal replacement therapy is associated with lack of renal recovery in patients with acute kidney injury.
      Each rise in percent of fluid overload at dialysis initiation was a significant negative predictor of kidney recovery (hazard ratio 0.97, [0.95-1.0]). Similar results were obtained for 1-year survival (OR 0.96; 95% CI 0.92- 0.99).

      Fluid Management and AKI Diagnosis

      A subsequent analysis of the FACTT trial suggested that adjusting serum creatinine for fluid balance may influence AKI diagnosis and prognosis.
      • Liu K.D.
      • Thompson B.T.
      • Ancukiewicz M.
      • et al.
      Acute kidney injury in patients with acute lung injury: Impact of fluid accumulation on classification of acute kidney injury and associated outcomes.
      Patients with AKI identified after but not before adjusting for positive fluid balance had higher mortality rates (31% vs 12%, P < 0.001), and patients who had AKI before but not after adjusting for fluid balance had lower mortality rates after adjustment (31% vs 11%, P = 0.005). Another study showed that correcting serum creatinine for fluid balance improved AKI staging.
      • Macedo E.
      • Bouchard J.
      • Soroko S.H.
      • et al.
      Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients.
      Future studies should consider adjusting serum creatinine for fluid balance and assessing the effect of these adjustments on AKI diagnosis and prognosis.
      In summary, results from observational studies suggest that a conservative fluid approach may be beneficial in terms of mortality and kidney recovery in patients with severe AKI; however, RCTs are required to confirm these findings before any clear recommendation can be made. The type of fluids used should also be included in these studies. Regarding fluid overload as a threshold for RRT initiation in AKI, physicians from a multicenter pediatric study recently agreed that initiating RRT within 24-48 hours of reaching more than 10% fluid overload is clinically acceptable (NCT01416298). To our knowledge, there are no ongoing adult studies on fluid overload in AKI requiring RRT, and this threshold has not been formally adopted for adult patients. Finally, the influence of fluid balance on serum creatinine should also be taken into account to diagnose AKI and assess its prognosis.

      Diuretics

      Patients with AKI can develop oliguria and fluid retention, which are associated with further complications such as respiratory failure. In many studies, oliguric AKI has been associated with worse outcomes than nonoliguric AKI.
      • Frankel M.C.
      • Weinstein A.M.
      • Stenzel K.H.
      Prognostic patterns in acute renal failure: The New York Hospital, 1981-1982.
      • Klahr S.
      • Miller S.B.
      Acute oliguria.
      • Brivet F.G.
      • Kleinknecht D.J.
      • Loirat P.
      • Landais P.J.
      Acute renal failure in intensive care units—Causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. French Study Group on Acute Renal Failure.
      The use of diuretics in oliguric AKI is frequent; however, the benefit associated with this intervention remains unproven.
      • Klahr S.
      • Miller S.B.
      Acute oliguria.
      • Brivet F.G.
      • Kleinknecht D.J.
      • Loirat P.
      • Landais P.J.
      Acute renal failure in intensive care units—Causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. French Study Group on Acute Renal Failure.
      • DePriest J.
      Reversing oliguria in critically ill patients.
      Experimental studies have shown that furosemide could reduce AKI risk by inhibiting the Na-K-2Cl cotransporter to reduce tubular medullar oxygen demand.
      • Rosenberger C.
      • Heyman S.N.
      • Rosen S.
      • et al.
      Up-regulation of HIF in experimental acute renal failure: Evidence for a protective transcriptional response to hypoxia.
      Increased production of prostaglandins could also have a role.
      • Kramer H.J.
      • Schuurmann J.
      • Wassermann C.
      • Dusing R.
      Prostaglandin-independent protection by furosemide from oliguric ischemic renal failure in conscious rats.
      Although interesting, the results of these experimental animal studies might not translate in humans.
      • Oppermann M.
      • Hansen P.B.
      • Castrop H.
      • Schnermann J.
      Vasodilatation of afferent arterioles and paradoxical increase of renal vascular resistance by furosemide in mice.
      • Kallskog O.
      • Nygren K.
      • Wolgast M.
      Failure of loop diuretics to improve the long term outcome of ischaemic damage in rat kidneys.
      • Heyman S.N.
      • Brezis M.
      • Greenfeld Z.
      • Rosen S.
      Protective role of furosemide and saline in radiocontrast-induced acute renal failure in the rat.
      We will review the use of diuretics for the prevention and treatment of AKI.

      Diuretics in Prevention of AKI

      Several years ago, RCTs reported that loop diuretics do not prevent AKI.
      • Lassnigg A.
      • Donner E.
      • Grubhofer G.
      • Presterl E.
      • Druml W.
      • Hiesmayr M.
      Lack of renoprotective effects of dopamine and furosemide during cardiac surgery.
      • Hager B.
      • Betschart M.
      • Krapf R.
      Effect of postoperative intravenous loop diuretic on renal function after major surgery.
      More recently, Mahesh and colleagues evaluated the renoprotective effect of low-dose furosemide or saline infusion for 12 hours in 42 cardiac surgical patients (Table 3).
      • Mahesh B.
      • Yim B.
      • Robson D.
      • Pillai R.
      • Ratnatunga C.
      • Pigott D.
      Does furosemide prevent renal dysfunction in high-risk cardiac surgical patients? Results of a double-blinded prospective randomised trial.
      There were no differences in kidney function between groups, and urine output was higher in the furosemide group. The small number of patients and the short period of furosemide infusion limit the generalization of these results. A recent meta-analysis by Ho and Power also concluded that preventive furosemide administration does not improve the risk of RRT or mortality.
      • Ho K.M.
      • Power B.M.
      Benefits and risks of furosemide in acute kidney injury.
      On the basis of these results, the recent KDIGO guidelines recommended not using furosemide to prevent AKI (grade 1B).
      KDIGO AKI Guideline.
      Table 3Diuretics in Prevention and Treatment of AKI
      Author, YearStudy TypePatients Number (n) and CharacteristicsPatients Number (n) on Diuretics; Specific Types (%) and DosesPatients Without Diuretics (or on Low Dose)AKI Definition or Evaluation of Kidney FunctionOutcomesComments
      Prevention of AKI
       Mahesh, 2008
      • Mahesh B.
      • Yim B.
      • Robson D.
      • Pillai R.
      • Ratnatunga C.
      • Pigott D.
      Does furosemide prevent renal dysfunction in high-risk cardiac surgical patients? Results of a double-blinded prospective randomised trial.
      RCTn = 50, cardiac surgical patients at risk for AKI
      Risk of AKI defined by one or more of the following criteria: creatinine >1.5 mg/dL, left ventricular ejection fraction <50%, diabetes, combined coronary-aortic bypass and valve surgery, redo cardiac surgery.
      n = 21 furosemide 4 mg/h for 12 h after surgeryn = 21, saline 2 mL/h for 12 h after surgeryCreatinine >1.47 mg/dL or increase of 50% if already over 1.47 mg/dL
      To convert serum creatinine in mg/dL to mol/L, multiply by 88.4; to convert urea nitrogen in mg/dL to mmol/L, multiply by 0.357.
      Kidney function: no differenceHigher diuresis in the furosemide group
      Treatment of AKI
       Mehta, 2002
      • Mehta R.L.
      • Pascual M.T.
      • Soroko S.
      • Chertow G.M.
      Group PS
      Diuretics, mortality, and nonrecovery of renal function in acute renal failure.
      Retrospective cohortn = 552, AKI in ICUn = 326, furosemide (62%) 80 mg, bumetanide (59%) 10 mg, metolazone (33%) 10 mgn = 226, no diureticsBUN >40 mg/dL, creatinine >2.0 mg/dL, or sustained rise creatinine of 1 mg/dL for CKD patientsMortality: OR 1.68 (1.06-2.64)

      Nonrecovery of kidney function: OR 1.79 (1.19-2.68)
      Higher risk of death or nonrecovery with a ratio of daily furosemide dose on total 24 h diuresis >1.0, OR 2.94 (1.61-5.36)
       Uchino, 2004
      • Uchino S.
      • Doig G.S.
      • Bellomo R.
      • et al.
      Diuretics and mortality in acute renal failure.
      Prospective cohortn = 1743, AKI in ICUn = 1117, furosemide (98.3%) 240 mg dailyn = 626, no diureticsRRT requirement, and/or urine output <200 mL in 12 h, and/or BUN >86 mg/dL, and/or serum potassium >6.5 mEq/LMortality: no differenceThree different statistic models reproduced the same results
       Cantarovich, 2004
      • Cantarovich F.
      • Rangoonwala B.
      • Lorenz H.
      • Verho M.
      • Esnault V.L.M.
      Group H-DFiARFS
      High-dose furosemide for established ARF: A prospective, randomized, double-blind, placebo-controlled, multicenter trial.
      RCTn = 338, AKI and RRT (ICU or nephrology units)n = 166, furosemide 25 mg/kg/d IV (max 2 g) or 35 mg/kg/d orallyn = 164, placeboRRT independenceMortality: no difference Kidney function: no differenceHigh-dose furosemide decreased time to achieve 2-L/d diuresis but no difference in number and duration of dialysis sessions
       Van der Voort, 2009
      • van der Voort P.H.J.
      • Boerma E.C.
      • Koopmans M.
      • et al.
      Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: A double blind randomized controlled trial.
      RCTn = 71, CVVH in ICUn = 36, furosemide 0.5 mg/kg/h started at CVVH discontinuationn = 35, placebo infusionRRT independenceKidney function: no differenceDiuretics increased urine output and sodium excretion
       Grams, 2011
      • Grams M.E.
      • Estrella M.M.
      • Coresh J.
      • Brower R.G.
      • Liu K.D.
      • National Heart Lung, and Blood Institute Acute Respiratory Distress Syndrome Network
      Fluid balance, diuretic use, and mortality in acute kidney injury.
      Retrospective (data collected prospectively)n = 306, AKIn = 169 conservative fluid therapy; furosemide, mean dose 80 mg/dn = 137 liberal fluid therapy; furosemide 23 mg/d50% or 0.3-mg/dL increase in creatinine from baseline, occurring over ≤48 hMortality: no effect of furosemide dose after adjustment for fluid balanceMortality OR 0.38 (0.23-0.63) for furosemide dose before fluid balance adjustment
      Abbreviations: BUN, blood urea nitrogen; CVVH, continuous venovenous hemofiltration.
      Risk of AKI defined by one or more of the following criteria: creatinine >1.5 mg/dL, left ventricular ejection fraction <50%, diabetes, combined coronary-aortic bypass and valve surgery, redo cardiac surgery.
      To convert serum creatinine in mg/dL to mol/L, multiply by 88.4; to convert urea nitrogen in mg/dL to mmol/L, multiply by 0.357.

      Diuretics in Treatment of AKI

      Numerous studies have been conducted to evaluate the effect of furosemide in treating AKI with conflicting results. We agree with the KDIGO guidelines that diuretics should not be used to treat AKI, except for the management of volume overload (grade 2C).
      KDIGO AKI Guideline.
      In the meta-analysis by Ho and Power, the use of diuretics in the treatment of AKI was not associated with a significant modification of the risk of mortality or RRT requirement.
      • Ho K.M.
      • Power B.M.
      Benefits and risks of furosemide in acute kidney injury.
      Six RCTs reported data on mortality and 5 studies reported data on RRT requirement. A significant proportion of these studies were conducted more than 15 years ago, and fluid balance was not reported, which could have influenced the results.
      More recent observational studies have confirmed that diuretics seem to have a neutral effect on outcomes after multivariable adjustments. The BEST kidney study, the largest prospective observational study in severe AKI, reported data on 1743 ICU patients.
      • Uchino S.
      • Doig G.S.
      • Bellomo R.
      • et al.
      Diuretics and mortality in acute renal failure.
      After adjustments, diuretic use was not associated with a significantly increased risk of mortality. Fluid balance was not reported in this study. More recently, data from the FACTT trial were used to assess the association between fluid balance and diuretic use in mortality.
      • National Heart Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network
      • Wiedemann H.P.
      • Wheeler A.P.
      • et al.
      Comparison of two fluid-management strategies in acute lung injury.
      Among the 1000 patients from the original study, 306 developed AKI within the first 2 days of the study.
      • Grams M.E.
      • Estrella M.M.
      • Coresh J.
      • Brower R.G.
      • Liu K.D.
      • National Heart Lung, and Blood Institute Acute Respiratory Distress Syndrome Network
      Fluid balance, diuretic use, and mortality in acute kidney injury.
      Higher furosemide doses were associated with decreased mortality at 60 days (OR 0.38; 95% CI 0.23-0.63); however, this association became nonsignificant after adjustment for post-AKI fluid balance (OR 0.73; 95% CI 0.42-1.26). These results could be explained by the effect of fluid overload, and not diuretics per se, on mortality. In contrast, an older retrospective study found that diuretic use was associated with an increased risk of death (OR 1.68; 95% CI 1.06-2.64), and these results were driven by patients receiving high doses of diuretics, perhaps representing a relative unresponsiveness.
      • Mehta R.L.
      • Pascual M.T.
      • Soroko S.
      • Chertow G.M.
      Group PS
      Diuretics, mortality, and nonrecovery of renal function in acute renal failure.
      This study was criticized for collinearity in the covariable analysis and nonoptimal statistical methods. In addition, fluid balance was not reported.

      Diuretics in Treatment of AKI with RRT

      Two RCTs recently showed that loop diuretics do not improve recovery of kidney function in AKI requiring RRT. In the largest RCT on furosemide in AKI, patients were randomized to furosemide at 25 mg/kg/day intravenously, or furosemide at 35 mg/kg/day orally, or matched placebo.
      • Cantarovich F.
      • Rangoonwala B.
      • Lorenz H.
      • Verho M.
      • Esnault V.L.M.
      Group H-DFiARFS
      High-dose furosemide for established ARF: A prospective, randomized, double-blind, placebo-controlled, multicenter trial.
      Patients were randomized before RRT initiation, and furosemide was administered after RRT initiation. There were no differences in survival or kidney recovery rates between the groups. Patients with high-dose furosemide had a higher urine output, but this did not translate into differences in the number of dialysis sessions or time on dialysis. In a smaller RCT, furosemide infusion (0.5 mg/kg/hour) started at the end of the continuous venovenous hemofiltration compared with placebo did not significantly improve kidney recovery.
      • van der Voort P.H.J.
      • Boerma E.C.
      • Koopmans M.
      • et al.
      Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: A double blind randomized controlled trial.
      Once again, urinary output (median 247 mL/hour vs 117 mL/hour, P = 0.003) and sodium excretion were higher in the group treated with furosemide.
      In summary, the use of diuretics in AKI has no clear benefit on the recovery of kidney function and mortality, and their role in preventing or treating fluid overload needs to be evaluated. Therefore, we agree with the KDIGO guidelines that diuretics should not be used to treat AKI, except for treating volume overload.
      KDIGO AKI Guideline.
      Two ongoing studies might bring new insights to these clinically relevant questions. The SPARK study is a phase II randomized, blinded, placebo-controlled trial of a low-dose infusion of furosemide titrated to urine output in critically ill patients with early AKI.
      • Bagshaw S.M.
      • Gibney R.T.N.
      • 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.
      The study is expected to enroll 216 critically ill patients and its primary outcome is progression in AKI severity. Secondary outcomes include fluid balance, need for RRT, duration of AKI, rate of kidney recovery, and mortality. The study should soon be completed. Another study, ”The Effect of Loop Diuretics on Severity and Outcome of Acute Kidney Injury”, will evaluate the effect of 1.0 or 1.5 mg/kg/hour of intravenous furosemide on kidney recovery. This prospective, nonrandomized trial is expected to enroll 150 patients and should be completed by 2015.

      Conclusion

      There is increasing evidence suggesting that isotonic crystalloids should be used instead of colloids as initial management for expansion of intravascular volume in patients at risk for AKI or with AKI, such as those with sepsis, septic shock, or trauma. The optimal timing and amount of initial volume resuscitation to prevent AKI, to reduce its severity, and to improve mortality still needs to be defined. A more aggressive fluid repletion in the early setting is probably beneficial. Once AKI occurs and that hemodynamic status is stabilized, the relevance of a restrictive fluid balance and the use of diuretics or RRT to prevent or treat fluid overload and improve outcomes in this population, without worsening kidney function, needs to be confirmed with RCTs. Ongoing studies, such as SPARK
      • Bagshaw S.M.
      • Gibney R.T.N.
      • 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.
      and ”The Effect of Loop Diuretics on Severity and Outcome of Acute Kidney Injury” might bring new insights on these questions.

      References

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