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 Table of Contents  
Year : 2019  |  Volume : 1  |  Issue : 2  |  Page : 52-56

Pragmatic Studies for Acute Kidney Injury: Fluid Resuscitation in the Peri-Acute Kidney Injury Period

1 Department of Critical Care Medicine, Center for Critical Care Nephrology, CRISMA, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
2 Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
3 Department of Anesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Lyon, France
4 Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
5 Department of Critical Care Medicine, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
6 Department of Nephrology, Dialysis and Transplantation, International Renal Research Institute of Vicenza, San Bortolo Hospital, Vicenza, Italy

Date of Submission21-Aug-2018
Date of Acceptance08-Mar-2019
Date of Web Publication27-Sep-2019

Correspondence Address:
Prof. Raghavan Murugan
Department of Critical Care Medicine, Center for Critical Care Nephrology, CRISMA, University of Pittsburgh School of Medicine, 3347 Forbes Avenue, Suite 220, Rm 206, Pittsburgh, Pennsylvania 15213
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jtccm.jtccm_10_18

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How fluid resuscitation clinical trials should be conducted for either prevention or treatment of acute kidney injury among patients admitted to the intensive care unit is unclear. In 2017, a group of experts in fluid resuscitation and acute kidney injury met at the Acute Disease Quality Initiative (ADQI) XIX consensus conference on “Pragmatic Studies for AKI”, Wuhan, China and developed a research framework. In this report, we summarize the consensus recommendations on the topic of fluid resuscitation in the peri-AKI period based on existing clinical evidence. We also discuss the gaps in our knowledge and identify future research questions. Finally, we examine the feasibility of conducting a pragmatic fluid resuscitation trial to improve outcomes from acute kidney injury.

Keywords: Acute kidney injury, fluid management, pragmatic trials

How to cite this article:
Murugan R, Qiu H, Rimmele T, Li J, Peng Z, Yu K, Kellum JA, Ronco C. Pragmatic Studies for Acute Kidney Injury: Fluid Resuscitation in the Peri-Acute Kidney Injury Period. J Transl Crit Care Med 2019;1:52-6

How to cite this URL:
Murugan R, Qiu H, Rimmele T, Li J, Peng Z, Yu K, Kellum JA, Ronco C. Pragmatic Studies for Acute Kidney Injury: Fluid Resuscitation in the Peri-Acute Kidney Injury Period. J Transl Crit Care Med [serial online] 2019 [cited 2023 Mar 29];1:52-6. Available from: http://www.tccmjournal.com/text.asp?2019/1/2/52/268082

  Introduction Top

Intravenous fluids are commonly administered to expand intravascular volume and to correct hypovolemia in critically ill patients who are at risk for acute kidney injury (AKI). Conceptually, resuscitation fluids can be administered either to prevent AKI or to promote recovery from AKI [Figure 1]. Several characteristics of fluids such as the fluid type, timing and rate of administration, and volume may potentially influence the risk of AKI and outcomes associated with AKI in critically ill patients. For instance, administration of hydroxyethyl starch has been associated with increased risk of AKI and mortality in patients with severe sepsis.[1] Recent studies also show that in patients presenting with septic shock to the emergency department, goal-directed fluid resuscitation strategy neither prevents AKI nor promotes recovery from AKI.[2]
Figure 1: Conceptual model for fluid resuscitation trial in the peri-acute kidney injury period. A pragmatic fluid resuscitation trial can be designed for the prevention of acute kidney injury in high-risk patients after exposure to risk factors in susceptible individuals. Such trial can also be designed to improve renal recovery after the development of acute kidney injury

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Thus, it is unclear whether the use of resuscitation fluids is associated with lower risk of AKI or resolution of AKI. Furthermore, there is no framework for how fluid resuscitation trials should be designed for the prevention or treatment of AKI. In 2017, a group of experts in fluid resuscitation and AKI met at the Acute Disease Quality Initiative (ADQI) XIX consensus conference on “Pragmatic Studies for AKI,” Wuhan, China, on April 2–5, and developed a list of the key questions [Table 1]. In this report, we summarize the consensus recommendations on the topic of fluid resuscitation in the peri-AKI period based on existing clinical evidence. We also discuss the gaps in our knowledge and identify future research questions.
Table 1: Questions identified by the consensus group

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  Results Top

Which fluid/fluid combination is more effective for correction of hypovolemia in high-risk patients?

Resuscitation fluids are broadly classified as colloid and crystalloid solutions. Colloidal solutions contain molecules that are suspended in a carrier solution and are incapable of crossing the semipermeable capillary membrane owing to the higher molecular weight of various molecules. Examples of colloids include albumin, hydroxyethyl starch, gelatin, and dextran. Crystalloid solutions typically contain concentrations of sodium and chloride ions to maintain tonicity and are freely permeable across the semipermeable capillary membrane. Administration of large volumes of 0.9% saline results in hyperchloremia. Balanced solutions contain anions other than chloride and are associated with reduced risk of hyperchloremia. Examples of balanced crystalloids include lactated ringers, Ringer's acetate, and plasmalyte.

Although the volume-sparing effect of colloids is considered as an advantage as it stays in the intravascular space for longer than crystalloids, no significant difference in 28-day mortality as well as in hemodynamic endpoints, such as mean arterial pressure or heart rate, was observed in a large clinical trial of saline versus albumin resuscitation in critically ill patients.[3] Nevertheless, the use of albumin was associated with a significant but clinically small increase in central venous pressure and the ratio of the volumes of albumin to the volumes of saline administered to achieve these endpoints was observed to be only of 1:1.4.[3],[4] Another, more recent study that compared colloids versus crystalloids in patients with hypovolemia also found no difference in 28-day mortality.[5] Hydroxyethyl starch is associated with increased risk of AKI in patients with sepsis [1] and increased risk of renal replacement therapy among critically ill patients.[6] Pooled meta-analysis of several clinical trials shows that the use of hydroxyethyl starch is associated with increased risk of AKI.[7]

A sequential period trial found that the liberal use of chloride-containing solution such as 0.9% saline is associated with increased risk of AKI compared to a strategy of chloride-restrictive resuscitation.[8] However, large randomized clinical trials showed no difference in risk of AKI in critically ill patients who receive saline resuscitation compared with buffered electrolyte solution such as plasmalyte.[9],[10] Thus, the choice between crystalloids and colloids for resuscitation should not be based on hemodynamic endpoints per se but rather should be based on other physiologic reasons. For instance, colloids could be used to limit fluid overload as fluid overload had been shown to be independently associated with mortality in observational studies.[11],[12] Similarly, balanced electrolyte solutions could be used in patients at risk or with hyperchloremia since hyperchloremia is associated with a number of unwanted effects such as altered intra-renal hemodynamics, coagulopathy, and gastrointestinal symptoms.[13],[14]

How much fluids should be given for treatment of hypovolemia in patients with oliguric acute kidney injury?

Oliguria is the second most common reason for fluid administration after hypotension in critically ill patients.[15] However, there is very limited evidence that the treatment of oliguria with fluid administration is associated with improved outcomes. Although no recommendations can be made on how much fluid should be administered, oliguria should serve as a biomarker for investigation for AKI including assessment of hemodynamics and renal hypoperfusion, nephrotoxin exposure, rather than default fluid administration.

What to do in patients with oliguric acute kidney injury who continue to have hypovolemia and worsening/new tissue edema?

Oliguric patients are at a high risk for fluid overload, which is independently associated with poor outcomes.[11] In a recent point prevalent study of fluid challenge in critically ill patients, no hemodynamic monitoring was used to guide fluid therapy in 43% of patients, and dynamic measures of preload responsiveness were used only in 22% of patients.[15] While the judicious use of fluids may be warranted in hypovolemic patients who are preload responsive, fluid administration must be used with caution in patients who continuously remain preload responsive and oliguric as fluid overload may worsen tissue edema impairing oxygenation and also impair repair recovery of renal function.[16] However, there are no well-designed clinical studies to answer this key clinical question.

What should be the outcome of fluid resuscitation trials in patients with established acute kidney injury?

Selection of the appropriate endpoint is pivotal for fluid resuscitation trials designed to improve outcomes from AKI. For trials designed to improve short-term recovery from early AKI (e.g.,kidney disease improving global outcome (KDIGO) Stage 1 or only biomarker-positive AKI), progression to KDIGO Stage II or III or the use of dialysis per se could be defined as an endpoint for the trial.[17] It is also important to note that when AKI is ascertained using serum creatinine, administration of large volumes of fluid could confound the ascertainment of AKI or its severity due to hemodilution.[18] It is also important that the timing of recovery is incorporated into the endpoint as delayed recovery or nonrecovery might be influenced by several other interventions other than fluid administration and is also associated with different prognoses.[19]

Long-term outcomes from AKI could be examined using “hard” and “patient-centered” outcomes such as death, dialysis dependence, or persistent renal dysfunction suggesting onset of chronic kidney disease (CKD). The composite outcome of death, new dialysis, and worsened kidney function, defined as a 25% or 50% decline in estimated glomerular filtration rate, constitutes the major adverse kidney event (MAKE) outcome. MAKE30, MAKE60, and MAKE90 are assessed after 30, 60, and 90 days, respectively. MAKE90 is a frequent endpoint because this is typically the time point when CKD is diagnosed after AKI. Using a composite outcome increases the event rate and thus decreases the sample size requirement for conducting the studies. However, composite outcomes are problematic when individual components are affected differently by the intervention.

  Standardization of Care for Acute Kidney Injury Recovery (Star) Trial Top

What pragmatic fluid resuscitation trial should be designed to improve outcomes from acute kidney injury in China?

Since sepsis is the leading cause of AKI in critically ill patients worldwide with intra-abdominal sepsis being the most common in Chinese ICUs, the consensus group considered designing a fluid trial for prevention of AKI in patients with intra-abdominal sepsis. Nevertheless, recent evidence from cohorts of patients with sepsis suggest that two-thirds of patients already have AKI at the time of presentation to the emergency room by serum creatinine.[2],[20] Thus, the consensus group opined that clinical trial for the prevention of AKI in patients with sepsis may not be feasible, but rather, interventions should focus to improve outcomes after the development of sepsis-induced AKI.

The consensus group then considered designing a fluid resuscitation protocol using crystalloids and colloids that are readily available in China. [Table 2] shows the various factors that should be considered while designing interventional fluid trials. Following extensive discussion, it became apparent that the current standard of care with regard to fluid use in Chinese ICUs is highly variable and is unclear. Thus, the ADQI group proposed a two-step iterative process for designing a pragmatic clinical trial. First, it was recommended that a multicenter observational study is conducted to understand and identify current best practices of fluid use across Chinese ICUs in patients with intra-abdominal sepsis who undergo surgery and develop AKI. Recommendations were made for very detailed and high granular data collection to identify best practices that are associated with better outcomes.
Table 2: Considerations for designing fluid resuscitation trials

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Second, the group proposed to protocolize the best practices in Chinese ICUs with regard to fluid management, into an intervention. A pragmatic clinical trial should then be designed to compare the protocolized “best” practice care versus usual care in patients with intra-abdominal sepsis who undergo surgery. Inclusion criteria should consist of patients with intra-abdominal sepsis who undergo exploratory laparotomy and develop AKI diagnosed either using the KDIGO definition or detected by a sensitive or predictive biomarker within 24 h following surgery.

Primary outcome should include those who are alive and recovered from AKI within 7 days defined as return to <150% of baseline serum creatinine without the need for renal replacement therapy. Secondary outcomes should include MAKE including either individual or composite of death, dialysis dependence, or persistent renal dysfunction at hospital discharge at day 30 (MAKE30). MAKE30 was proposed as an outcome since the assessment of long-term outcomes might pose logistic issues related to patient follow-up postdischarge in China.

What are the effect and sample size considerations for the STAR trial?

In a recently completed study of renal recovery in a large cohort of critically ill patients, nearly 64% of patients had early resolution of AKI within the first 7 days of hospitalization.[19] Of patients who recovered from early AKI, 27% of patients continued to recover in the 2nd week, 22.5% of patients have relapse of AKI and then recover subsequently, and 15% of patients had relapse of AKI and never recovered from AKI. Of patients who never recovered early from AKI, 26.5% never ever recovered and 9.7% recovered late.

[Table 3] shows the hypothesized sample size calculation for absolute risk reductions (ARRs) of 5% and 10% with protocolized care to enhance renal recovery. Using above data from Kellum et al.,[19] we varied the baseline renal recovery rate in the control arm between 50% and 70% [Table 3] for an ARR of 5% and 10%. We estimated that the sample size required per arm would vary between 2500 and 3120 patients for 5% ARR and between 580 and 770 for 10% ARR by the protocolized care [Table 3].
Table 3: Effect and sample size considerations for STAR trial

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If hospital mortality is used as an endpoint, for an ARR of 2.2% and a number needed to treat of 45, assuming 22.7% mortality in the control arm, would require 37,452 patients to show a difference in outcome with the protocolized care, which would translate into 2222 lives saved for every 100,000 patients with AKI. However, the consensus group proposed that renal recovery, rather than mortality, be used as an outcome for the clinical trial due to feasibility issues related to recruiting a large cohort of patients to show small difference in mortality.

  Conclusions Top

Fluids are commonly administered to correct hypovolemia and to prevent or improve recovery from AKI. Whether this practice is associated with improved outcomes, however, is unclear. Choice between colloids and crystalloids for resuscitation should be based on physiologic rationale rather than hemodynamic endpoints and individual needs of the patient. A pragmatic clinical trial is warranted to examine whether a protocolized care using fluids in patients with sepsis-induced AKI is associated with renal recovery.

Financial support and sponsorship


Conflicts of interest

Dr. Murugan has received grant funding from La Jolla pharmaceuticals, Bioporto, and fee for conduct of clinical studies in AKI from AM Pharma and La. Jolla Inc.

  References Top

Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Šneman A, et al. Hydroxyethyl starch 130/0.42 versus ringer's acetate in severe sepsis. N Engl J Med 2012;367:124-34.  Back to cited text no. 1
Kellum JA, Chawla LS, Keener C, Singbartl K, Palevsky PM, Pike FL, et al. The effects of alternative resuscitation strategies on acute kidney injury in patients with septic shock. Am J Respir Crit Care Med 2016;193:281-7.  Back to cited text no. 2
Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R, et al. A comparison of albumin and saline for fluid resuscitation in the Intensive Care Unit. N Engl J Med 2004;350:2247-56.  Back to cited text no. 3
Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med 2013;369:2462-3.  Back to cited text no. 4
Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declère AD, et al. Effects of fluid resuscitation with colloids vs. crystalloids on mortality in critically ill patients presenting with hypovolemic shock: The CRISTAL randomized trial. JAMA 2013;310:1809-17.  Back to cited text no. 5
Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;367:1901-11.  Back to cited text no. 6
Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: A systematic review and meta-analysis. JAMA 2013;309:678-88.  Back to cited text no. 7
Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M, et al. Association between a chloride-liberal vs. chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012;308:1566-72.  Back to cited text no. 8
Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, et al. Effect of a buffered crystalloid solution vs. saline on acute kidney injury among patients in the Intensive Care Unit: The SPLIT randomized clinical trial. JAMA 2015;314:1701-10.  Back to cited text no. 9
Semler MW, Wanderer JP, Ehrenfeld JM, Stollings JL, Self WH, Siew ED, et al. Balanced crystalloids versus saline in the Intensive Care Unit. The SALT randomized trial. Am J Respir Crit Care Med 2017;195:1362-72.  Back to cited text no. 10
Balakumar V, Murugan R, Sileanu FE, Palevsky P, Clermont G, Kellum JA, et al. Both positive and negative fluid balance may be associated with reduced long-term survival in the critically ill. Crit Care Med 2017;45:e749-57.  Back to cited text no. 11
RENAL Replacement Therapy Study Investigators, Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, et al. An observational study fluid balance and patient outcomes in the randomized evaluation of normal vs. augmented level of replacement therapy trial. Crit Care Med 2012;40:1753-60.  Back to cited text no. 12
Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983;71:726-35.  Back to cited text no. 13
Kiraly LN, Differding JA, Enomoto TM, Sawai RS, Muller PJ, Diggs B, et al. Resuscitation with normal saline (NS) vs. lactated ringers (LR) modulates hypercoagulability and leads to increased blood loss in an uncontrolled hemorrhagic shock swine model. J Trauma 2006;61:57-64.  Back to cited text no. 14
Cecconi M, Hofer C, Teboul JL, Pettila V, Wilkman E, Molnar Z, et al. Fluid challenges in intensive care: The FENICE study: A global inception cohort study. Intensive Care Med 2015;41:1529-37.  Back to cited text no. 15
Prowle JR, Echeverri JE, Ligabo EV, Ronco C, Bellomo R. Fluid balance and acute kidney injury. Nat Rev Nephrol 2010;6:107-15.  Back to cited text no. 16
Kellum JA, Zarbock A, Nadim MK. What endpoints should be used for clinical studies in acute kidney injury? Intensive Care Med 2017;43:901-3.  Back to cited text no. 17
Liu KD, Thompson BT, Ancukiewicz M, Steingrub JS, Douglas IS, Matthay MA, et al. Acute kidney injury in patients with acute lung injury: Impact of fluid accumulation on classification of acute kidney injury and associated outcomes. Crit Care Med 2011;39:2665-71.  Back to cited text no. 18
Kellum JA, Sileanu FE, Bihorac A, Hoste EA, Chawla LS. Recovery after acute kidney injury. Am J Respir Crit Care Med 2017;195:784-91.  Back to cited text no. 19
Murugan R, Karajala-Subramanyam V, Lee M, Yende S, Kong L, Carter M, et al. Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival. Kidney Int 2010;77:527-35.  Back to cited text no. 20


  [Figure 1]

  [Table 1], [Table 2], [Table 3]


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