IVOIRE: High-Volume Hemofiltration in Septic Shock (2013)

“In this multicenter randomized controlled trial, we did not find a significant reduction in 28-day mortality with high-volume hemofiltration as compared with standard-volume hemofiltration in patients with septic shock and acute kidney injury.”

  • The IVOIRE Study Group

1. Publication Details

  • Trial Title: High-Volume Hemofiltration versus Standard-Volume Hemofiltration in Sepsis-Induced Acute Kidney Injury
  • Citation: Joannes-Boyau O, Honoré PM, Perez P, et al. High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial. Intensive Care Med. 2013;39(9):1535-1546. DOI: 10.1007/s00134-013-2967-z
  • Published: September 2013, in Intensive Care Medicine
  • Author: Olivier Joannes-Boyau, M.D.
  • Funding: French Ministry of Health; Gambro.

2. Keywords

  • Sepsis, Septic Shock, Acute Kidney Injury (AKI), High-Volume Hemofiltration (HVHF), Renal Replacement Therapy (RRT), Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with septic shock and acute kidney injury (Population), does a strategy of high-volume hemofiltration (HVHF) (Intervention) compared to standard-volume hemofiltration (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Septic shock is characterized by a massive inflammatory response. It was hypothesized that high-volume hemofiltration (HVHF), a form of continuous renal replacement therapy using a very high effluent rate, could improve outcomes not just by supporting the kidneys, but also by removing inflammatory mediators from the blood (a concept known as “blood purification”).
  • Knowledge Gap: While physiologically appealing and supported by small, observational studies, there was no high-quality evidence from a large randomized controlled trial to determine if this more aggressive and resource-intensive form of RRT was superior to standard-dose RRT in septic shock.
  • Proposed Hypothesis: The authors hypothesized that high-volume hemofiltration (70 ml/kg/hr) would be superior to standard-volume hemofiltration (35 ml/kg/hr) in reducing 28-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 17 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from March 2006 to April 2011.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with septic shock requiring vasopressor support and acute kidney injury requiring renal replacement therapy.
    • Exclusion Criteria: Included pre-existing end-stage renal disease, pregnancy, and a decision to withhold life-sustaining treatment.
  • Intervention: Patients received high-volume hemofiltration (HVHF) at a prescribed effluent dose of 70 ml/kg/hr for 96 hours.
  • Control: Patients received standard-volume hemofiltration (SVHF) at a prescribed effluent dose of 35 ml/kg/hr for 96 hours.
  • Management Common to Both Groups: All other aspects of ICU care, including the management of sepsis and vasopressors, were at the discretion of the treating clinicians according to international guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 140 patients would be required to have 80% power to detect a 20% absolute risk reduction in 28-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 28 days.
    • Secondary Outcomes: Included 90-day mortality, shock reversal, and ventilator-free days.

6. Key Results

  • Enrollment and Baseline: 140 patients were randomized (67 to HVHF and 73 to SVHF). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 28-day mortality. 32 of 67 patients (48%) in the HVHF group died, compared with 31 of 73 patients (42%) in the SVHF group (p=0.51).
  • Secondary Outcomes: There were no significant differences between the groups in 90-day mortality, shock reversal, or ventilator-free days.
  • Adverse Events: The incidence of adverse events, including electrolyte disturbances like hypophosphatemia, 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 0.51 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 an important clinical question.
  • Generalizability: The inclusion of 17 diverse ICUs increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of 28-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 findings are specific to the doses of hemofiltration used in this trial and may not apply to other “blood purification” techniques.
  • Other: The trial was relatively small, and the control group already received a relatively high dose of RRT (35 ml/kg/hr), which may have made it more difficult for the intervention to show a benefit.

10. Conclusion of the Authors

  • The authors concluded that in patients with septic shock and AKI, a strategy of high-volume hemofiltration did not reduce 28-day mortality compared to standard-volume hemofiltration.

11. To Summarize

  • Impact on Current Practice: This was an important “negative” trial that provided strong evidence against the routine use of high-volume hemofiltration in septic shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock and AKI requiring RRT.
    • Actionable Intervention: The results do not support the use of high-volume hemofiltration (70 ml/kg/hr). A standard dose (e.g., 20-35 ml/kg/hr) is appropriate.
  • What This Trial Does NOT Mean: This trial does NOT mean that other forms of blood purification are not effective. It only tested this specific modality and dose.
  • Implementation Caveats: The findings of this trial support the de-adoption of a more complex, labor-intensive, and expensive therapy that offers no clinical benefit over the standard of care.

12. Context and Related Studies

  • Building on Previous Evidence: The IVOIRE trial (2013) was designed to provide a definitive answer to a question that had been raised by smaller, promising but inconclusive studies.
  • Influence on Subsequent Research: The definitive neutral result of this trial, along with other similar trials, has been highly influential in shaping international guidelines, which do not recommend the routine use of high-volume hemofiltration for sepsis.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question.
  • Future Directions: The failure of this and other broad, untargeted “blood purification” therapies has shifted the focus of research towards more specific and targeted devices for removing endotoxin or other inflammatory mediators in selected patient populations.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a physiologically plausible but unproven and resource-intensive therapy.
  • Methods: The multicenter RCT design was appropriate and robust. The main methodological weakness is the open-label design. The use of a relatively high-dose “standard care” arm is a key point for interpretation.
  • Results: The study reported a clear neutral finding for its primary outcome and all major secondary outcomes.
  • 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 most modern ICUs. This is a classic example of a high-quality “negative” trial that was practice-changing by providing strong evidence that a more aggressive and expensive intervention is not superior to a well-delivered standard of care.

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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