TRISS (PILOT): Transfusion Thresholds in Septic Shock (2014)

“In patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among patients assigned to a hemoglobin threshold of 7 g per deciliter and those assigned to a threshold of 9 g per deciliter.”

— The TRISS Trial Group

1. Publication Details

  • Trial Title: Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock. 
  • Citation: Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371(15):1381-1391. DOI: 10.1056/NEJMoa1406617. Note: The trial you are referring to is the TRISS trial (Transfusion Requirements in Septic Shock), published in 2014. The “PILOT” trial was its smaller predecessor
  • Published: October 9, 2014, in The New England Journal of Medicine.
  • Author: Lars B. Holst, M.D.
  • Funding: Danish Council for Independent Research and others.

2. Keywords

Blood Transfusion, Septic Shock, Anemia, Hemoglobin, Transfusion Trigger, Red Blood Cells, Critical Illness.

3. The Clinical Question

In adult patients with septic shock who had anemia (Population), did a lower hemoglobin threshold for transfusion (7 g/dL) (Intervention) compared to a higher hemoglobin threshold (9 g/dL) (Comparison) affect 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The landmark TRICC trial had established the safety of a restrictive transfusion strategy (trigger of 7 g/dL) in a general ICU population. However, it was unclear if this strategy was safe for patients with septic shock, who have profound circulatory derangements and might theoretically benefit from the increased oxygen-carrying capacity provided by a higher hemoglobin level.
  • Knowledge Gap: There was a lack of high-quality, randomized trial evidence to guide transfusion practice specifically in the high-risk population of patients with septic shock.
  • Proposed Hypothesis: The authors hypothesized that a lower hemoglobin threshold for transfusion would be non-inferior or superior to a higher threshold with respect to 90-day mortality.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, parallel-group, superiority trial.
  • Setting: 32 intensive care units (ICUs) in Denmark, Norway, Sweden, and Finland.
  • Trial Period: Enrollment from December 2011 to December 2013.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) in the ICU with septic shock (requiring vasopressors) and a hemoglobin concentration of ≤9 g/dL.
    • Exclusion Criteria: Active bleeding, acute coronary syndrome, or life-threatening anemia.
  • Intervention: A lower transfusion threshold. One unit of leukoreduced RBCs was transfused if the hemoglobin level dropped to ≤7 g/dL.
  • Control: A higher transfusion threshold. One unit of leukoreduced RBCs was transfused if the hemoglobin level dropped to ≤9 g/dL.
  • Management Common to Both Groups: All other aspects of care, including the management of septic shock, were at the discretion of the local clinical team, guided by international guidelines.
  • Power and Sample Size: The trial was powered to detect a 5% absolute difference in 90-day mortality, requiring 1000 patients.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included rates of ischemic events, use of life support (mechanical ventilation, RRT), and number of blood units transfused.

6. Key Results

  • Enrollment and Baseline: 1005 patients were randomized, with 998 included in the final analysis (502 to the lower-threshold group, 496 to the higher-threshold group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality between the lower-threshold and higher-threshold groups (43.0% vs 45.1%; P=0.44).
  • Secondary Outcomes: There were no significant differences in the rates of ischemic events or in the use of life support. Patients in the lower-threshold group received a median of 1 unit of blood, compared to 4 units in the higher-threshold group.
  • Adverse Events: The rates of transfusion reactions and other adverse events were similar between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
  • Primary Outcome Analysis: The proportion of deaths at day 90 was compared between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 90 days with the lower threshold: 0.94 (95% CI, 0.78 to 1.09; P=0.44).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the RR as 0.94.
      • Clinical Meaning: An RR of 0.94 means there was a 6% lower relative risk of death in the lower-threshold group compared to the higher-threshold group, but this difference was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.78 to 1.09.
      • Clinical Meaning: Since this confidence interval is centered around the line of no effect (1.0) and is relatively narrow, it provides a precise estimate that there is no significant difference between the two strategies. The true effect is likely somewhere between a 22% benefit and a 9% harm.
    • P-value:
      • Calculation: The reported p-value was 0.44.
      • Clinical Meaning: The p-value of 0.44 is far above the 0.05 threshold, confirming that the observed result is very likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 45.1% – 43.0% = 2.1%.
      • Clinical Meaning: The restrictive strategy was associated with a non-significant 2.1% absolute reduction in the risk of death at 90 days.
    • Number Needed to Treat (NNT): Not applicable, as the intervention showed no benefit for the primary outcome.
  • Subgroup Analyses: There was no evidence of a different treatment effect in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, multicenter, randomized trial that provided a robust answer to a specific and important clinical question.
  • Generalizability: The inclusion of 32 diverse Scandinavian ICUs increases the external validity of the findings.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a strong, patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded to clinicians, which could introduce performance bias, though the primary outcome of mortality is objective.
  • External Validity (Generalizability): The results apply to patients with septic shock and may not be generalizable to other forms of shock.
  • Other: The trial protocol allowed for clinician discretion to transfuse outside the assigned threshold, which occurred in a small number of cases.

10. Conclusion of the Authors

“In patients with septic shock, transfusion at a lower hemoglobin threshold (7 g per deciliter) did not result in a significantly different 90-day mortality rate than transfusion at a higher threshold (9 g per deciliter).”

11. To Summarize

  • Impact on Current Practice: The TRISS trial was a landmark study that definitively extended the safety of a restrictive transfusion strategy to the high-risk population of patients with septic shock. It provided strong evidence to counter the theoretical concern that these patients required higher hemoglobin levels to maintain oxygen delivery. This has solidified a restrictive transfusion strategy as the standard of care for nearly all ICU patients, including those with septic shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients with septic shock who develop anemia.
    • Actionable Intervention: Adopt a restrictive transfusion strategy, using a hemoglobin threshold of 7.0 g/dL as the trigger for transfusion.
    • Expected Benefit: No difference in mortality or ischemic events compared to a liberal strategy, with a significant reduction in blood product use (a median of 3 fewer units per patient).
  • What This Trial Does NOT Mean: This trial does not mean the 7.0 g/dL trigger applies to all patients. Caution is still warranted in patients with septic shock complicated by active bleeding or an acute coronary syndrome, who were excluded from this study.
  • Implementation Caveats: Adopting a restrictive strategy is safe, reduces costs, and conserves a scarce resource.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was a direct successor to the TRICC trial (1999), specifically addressing the septic shock population that was a key area of uncertainty after TRICC.
  • Influence on Subsequent Research: The TRISS trial has largely settled the debate for transfusion thresholds in septic shock. Its findings are highly influential and have been incorporated into the Surviving Spasis Campaign and other international guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the optimal transfusion threshold in patients with septic shock who also have an acute coronary syndrome?
  • Future Directions: Research continues to refine transfusion practices, with a focus on patient blood management and understanding the effects of the age of stored blood.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, addressing a common intervention in a high-risk population where practice was uncertain.
  • Methods: The large, multicenter, randomized design was methodologically strong and provided a high level of evidence.
  • Results: The trial had a clear and robustly neutral result for its primary outcome of mortality, as well as for key safety outcomes. The large difference in blood use between groups was a critical finding.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to the global ICU community and provide a definitive, evidence-based rationale to adopt a restrictive transfusion strategy as the standard of care for patients with septic shock.

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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