IDEAL-ICU: Early vs. Delayed RRT in Septic Shock with AKI (2018)

“In this multicenter randomized controlled trial, we found no significant difference in 90-day mortality between an early and a delayed strategy for initiating renal replacement therapy in patients with septic shock and severe acute kidney injury.”

  • The IDEAL-ICU Investigators

1. Publication Details

  • Trial Title: Early versus Delayed Initiation of Renal Replacement Therapy for Severe Acute Kidney Injury in Critically Ill Patients With Septic Shock: A Multicenter, Randomized Controlled Trial
  • Citation: Barbar SD, Clere-Jehl R, Bourredjem A, et al. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018;379(15):1431-1442. DOI: 10.1056/NEJMoa1803213
  • Published: October 11, 2018, in The New England Journal of Medicine
  • Author: Sigismond D. Barbar, M.D.
  • Funding: French Ministry of Health

2. Keywords

  • Acute Kidney Injury (AKI), Renal Replacement Therapy (RRT), Sepsis, Septic Shock, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients with early-stage septic shock and severe acute kidney injury (Population), does an early strategy of initiating renal-replacement therapy (RRT) (Intervention) compared to a delayed strategy (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The optimal time to initiate renal-replacement therapy (RRT) for acute kidney injury (AKI) in septic shock was a major area of clinical uncertainty. Previous trials like AKIKI (2016) and ELAIN (2016) had produced conflicting results, with AKIKI suggesting a delayed strategy was safe and ELAIN suggesting an early strategy was beneficial.
  • Knowledge Gap: A definitive, multicenter trial was needed to clarify the optimal timing of RRT initiation specifically in the high-risk population of patients with both septic shock and severe AKI.
  • Proposed Hypothesis: The authors hypothesized that an early strategy for initiating RRT would be superior to a delayed strategy in reducing 90-day mortality in this patient population.

5. Study Design and Methods

  • Design: A multicenter, prospective, open-label, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 29 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from September 2012 to June 2016.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with septic shock who had severe AKI, defined as meeting the criteria for the “Failure” category of the RIFLE classification, and who were not receiving etomidate.
    • Exclusion Criteria: Included pre-existing end-stage renal disease and life-threatening complications mandating immediate RRT (e.g., severe hyperkalemia).
  • Intervention: An “early” strategy, where RRT was initiated within 12 hours of the patient meeting the criteria for RIFLE-Failure.
  • Control: A “delayed” strategy, where RRT was initiated only after a waiting period of 48 hours if renal recovery had not occurred, or earlier if an urgent indication developed.
  • Management Common to Both Groups: The choice of RRT modality was at the discretion of the treating clinicians. All other aspects of ICU care were managed according to standard practice.
  • Power and Sample Size: The authors calculated that a sample size of 860 patients would provide 80% power to detect an 11% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included RRT-free days, ventilator-free days, and ICU length of stay.

6. Key Results

  • Enrollment and Baseline: 488 patients were randomized (246 to the early group and 242 to the delayed group). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early for futility by the data and safety monitoring board after an interim analysis showed a very low probability of finding a significant benefit with the early strategy.
  • Primary Outcome: There was no significant difference in 90-day mortality. 138 of 246 patients (56%) in the early-strategy group died, compared with 128 of 242 patients (53%) in the delayed-strategy group (p=0.59).
  • Secondary Outcomes: There were no significant differences between the groups in RRT-free days or ventilator-free days. In the delayed-strategy group, 98 patients (40%) recovered kidney function and never required RRT.
  • Adverse Events: The incidence of complications, including catheter-related bloodstream infections, was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.59 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on a critical clinical question.
  • Generalizability: The pragmatic design and inclusion of 29 diverse ICUs make the findings highly generalizable to real-world practice.
  • Statistical Power: Although stopped early, the trial was large enough to confidently rule out a major benefit from the early strategy.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was specific to patients with both septic shock and severe AKI.
  • Other: The trial was stopped early for futility, which means it was underpowered to definitively rule out a smaller, but still potentially important, treatment effect.

10. Conclusion of the Authors

  • The authors concluded that in patients with septic shock and severe AKI, there was no significant benefit associated with an early strategy for RRT initiation.

11. To Summarize

  • Impact on Current Practice: This trial provided strong, high-quality evidence that a routine early RRT strategy is not beneficial in patients with septic shock and severe AKI. It strongly supported the safety and appropriateness of a “watchful waiting” approach.
  • Specific Recommendations:
    • Patient Selection: For critically ill patients with septic shock and severe AKI who do not have an immediate life-threatening indication for RRT.
    • Actionable Intervention: It is reasonable to adopt a delayed strategy, closely monitoring the patient for the development of urgent indications for RRT.
    • Expected Benefit: This strategy may allow a significant proportion of patients (40% in this trial) to recover kidney function without ever needing RRT, thereby avoiding the risks and costs of the procedure.
  • What This Trial Does NOT Mean: This trial does NOT mean that RRT should be withheld from patients who develop clear, life-threatening indications (e.g., severe hyperkalemia, severe acidosis, or severe fluid overload).
  • Implementation Caveats: A delayed strategy requires diligent and active monitoring to ensure that RRT is initiated promptly if and when an urgent indication arises.

12. Context and Related Studies

  • Building on Previous Evidence: The IDEAL-ICU trial (2018) was designed to help resolve the conflicting findings of the earlier AKIKI (2016) and ELAIN (2016) trials.
  • Influence on Subsequent Research: The findings of this trial were consistent with the larger AKIKI trial and were further confirmed by the very large STARRT-AKI trial (2020). Together, these trials have solidified the evidence base for a delayed RRT initiation strategy in the majority of critically ill patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal timing of RRT in specific subgroups of patients (e.g., those with less severe AKI or different underlying causes) remains an area of investigation.
  • Future Directions: Future research is focused on identifying biomarkers that could help predict which patients will recover kidney function and which will progress to needing RRT, allowing for a more personalized approach to timing.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and important clinical dilemma in the ICU for which there was conflicting evidence.
  • Methods: The multicenter RCT design was appropriate and robust. The main methodological weakness is the open-label design. The early termination for futility is a key point for interpretation.
  • Results: The study reported a clear neutral finding for its primary outcome. A key secondary finding was that a delayed strategy allowed a large proportion of patients to avoid RRT altogether without an increase in harm.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable to the care of ICU patients with septic shock and severe AKI. The trial provides strong support for a “watchful waiting” approach in patients without urgent indications for dialysis.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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