TRICC: Restrictive vs Liberal Transfusion in the ICU (1999) - ESBICM® | Educational Society of Bedside Intensive Care Medicine

TRICC: Restrictive vs Liberal Transfusion in the ICU (1999)

“A restrictive strategy of red-cell transfusion is at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients, with the possible exception of patients with acute myocardial infarction and unstable angina.”

— The TRICC Investigators

1. Publication Details

Trial Title: A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care.
Citation: Hébert PC, Wells G, Blajchman MA, et al; for the Transfusion Requirements in Critical Care Investigators, for the Canadian Critical Care Trials Group. A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care. N Engl J Med. 1999;340(6):409-417. doi:10.1056/NEJM199902113400601.
Published: February 11, 1999, in The New England Journal of Medicine.
Author: Paul C. Hébert, M.D., M.H.A.
Funding: Medical Research Council of Canada.

2. Keywords

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

3. The Clinical Question

In euvolemic, critically ill adult patients (Population), does a restrictive red blood cell transfusion strategy (hemoglobin trigger of 7 g/dL) (Intervention) compared to a liberal transfusion strategy (hemoglobin trigger of 10 g/dL) (Comparison) affect 30-day all-cause mortality (Outcome)?

4. Background and Rationale

Existing Knowledge: Anemia is extremely common in critically ill patients, and red blood cell (RBC) transfusions are frequently administered to increase oxygen-carrying capacity. The standard practice was to maintain hemoglobin levels at or above 10 g/dL.
Knowledge Gap: There was no high-quality evidence from randomized trials to support the 10 g/dL transfusion trigger. It was unknown if this liberal strategy improved outcomes or if a more restrictive strategy, which would avoid the known risks of transfusion (e.g., infection, immunomodulation, volume overload), was safer or more effective.
Proposed Hypothesis: The authors hypothesized that a restrictive transfusion strategy would be as safe as a liberal strategy and could potentially lead to improved outcomes by reducing the number of transfusions and associated complications.

5. Study Design and Methods

Design: A prospective, multicenter, randomized, controlled trial.
Setting: 25 tertiary care intensive care units (ICUs) in Canada.
Trial Period: Enrollment from November 1994 to November 1997.
Population:
- Inclusion Criteria: Adult patients (≥16 years) admitted to the ICU who were euvolemic after initial fluid resuscitation and had a hemoglobin concentration <9.0 g/dL within 72 hours of admission.
- Exclusion Criteria: Active bleeding, chronic anemia, pregnancy, or brain death.
Intervention: A restrictive transfusion strategy. RBCs were transfused if the hemoglobin concentration dropped below 7.0 g/dL, with a target of maintaining it between 7.0 and 9.0 g/dL.
Control: A liberal transfusion strategy. RBCs were transfused if the hemoglobin concentration dropped below 10.0 g/dL, with a target of maintaining it between 10.0 and 12.0 g/dL.
Management Common to Both Groups: All other aspects of critical care were at the discretion of the local clinical team.
Power and Sample Size: The trial was powered to detect a 5% absolute difference in 30-day mortality, requiring 820 patients.
Outcomes:
- Primary Outcome: All-cause mortality at 30 days.
- Secondary Outcomes: Included in-hospital mortality, 60-day mortality, and severity of organ dysfunction.

6. Key Results

Enrollment and Baseline: 838 patients were randomized (418 to the restrictive strategy, 420 to the liberal strategy). The groups were well-matched at baseline.
Trial Status: The trial was completed as planned.
Primary Outcome: Overall 30-day mortality was similar between the restrictive and liberal groups (18.7% vs 23.3%; P=0.11).
Secondary Outcomes: In-hospital mortality was significantly lower in the restrictive group (22.2% vs 28.1%; P=0.05). In pre-specified subgroup analyses, patients in the restrictive group who were less severely ill (APACHE II score ≤20) and younger (<55 years) had significantly lower 30-day mortality.
Adverse Events: Patients in the liberal-strategy group had a trend toward more frequent cardiac events (myocardial infarction, pulmonary edema).

7. Medical Statistics

Analysis Principle: An intention-to-treat analysis was performed.
Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
Primary Outcome Analysis: The proportion of deaths at day 30 was compared between the two groups.
Key Statistic(s) Reported: Relative Risk (RR) for death at 30 days with the restrictive strategy: 0.80 (95% CI, 0.62 to 1.04; P=0.11).
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 0.80.
  - Clinical Meaning: An RR of 0.80 means there was a 20% lower relative risk of death in the restrictive transfusion 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 0.62 to 1.04.
  - Clinical Meaning: The confidence interval suggests the true effect could be anywhere from a 38% benefit to a 4% harm. Because it just crosses the line of no effect (1.0), the result is not statistically significant.
- P-value:
  - Calculation: The reported p-value was 0.11.
  - Clinical Meaning: The p-value of 0.11 is above the conventional threshold of 0.05, indicating that the observed difference could be 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 = 23.3% – 18.7% = 4.6%.
  - Clinical Meaning: The restrictive strategy was associated with a non-significant 4.6% absolute reduction in the risk of death at 30 days.
- Number Needed to Treat (NNT):
  - Formula: NNT = 1 / ARR.
  - Calculation: NNT = 1 / 0.046 = 21.7.
  - Clinical Meaning: If the observed effect were true, approximately 22 patients would need to be treated with a restrictive strategy to prevent one additional death at 30 days.
Subgroup Analyses: A significant mortality benefit was seen with the restrictive strategy in younger (<55 years) and less sick (APACHE II ≤20) patients.

8. Strengths of the Study

Study Design and Conduct: This was a large, multicenter, randomized trial that was the first to provide high-quality evidence to challenge a long-standing dogma in medicine.
Generalizability: The inclusion of 25 diverse ICUs and a broad population of critically ill patients increases the external validity of the findings.
Patient-Centered Outcomes: The primary outcome of 30-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.
External Validity (Generalizability): The trial excluded patients with active bleeding and had few patients with active coronary artery disease, so the results may not apply to these specific groups. The blood products used were older on average than in current practice.
Other: The primary outcome was not statistically significant, with the benefit seen in secondary outcomes and subgroups.

10. Conclusion of the Authors

11. To Summarize

Impact on Current Practice: The TRICC trial was one of the most important and practice-changing trials in the history of critical care. It single-handedly dismantled the long-held “10/30 rule” (transfuse to a hemoglobin of 10 g/dL). It provided strong evidence that a restrictive transfusion strategy (trigger of 7 g/dL) is safe for most critically ill patients and may be superior in certain subgroups. This has led to a dramatic reduction in blood product use worldwide, improving patient safety and conserving a scarce resource.
Specific Recommendations:
- Patient Selection: For the general population of euvolemic, critically ill adult patients.
- Actionable Intervention: Adopt a restrictive transfusion strategy, using a hemoglobin threshold of 7.0 g/dL as the trigger for transfusion.
- Expected Benefit: At least equivalent outcomes to a liberal strategy, with significantly fewer transfusions and a potential for improved survival in younger, less severely ill patients.
What This Trial Does NOT Mean: This trial does not mean the 7.0 g/dL trigger applies to all patients. Caution is warranted in patients with active bleeding, acute coronary syndromes, or traumatic brain injury, who were not well-represented in this study.
Implementation Caveats: The decision to transfuse should always be individualized, but a restrictive strategy should be the default approach for most ICU patients.

12. Context and Related Studies

Building on Previous Evidence: TRICC was the foundational trial that challenged decades of dogma based on physiological principles rather than clinical evidence.
Influence on Subsequent Research: This trial spawned a new era of research into transfusion medicine. Its findings have been largely confirmed and extended by numerous subsequent trials in various clinical settings, including the TRISS trial (2014) in septic shock, the FOCUS trial (2011) in high-risk cardiac surgery, and the TRIPICU trial (2007) in pediatrics.

13. Unresolved Questions & Future Directions

Unresolved Questions: What is the optimal transfusion threshold in specific populations not well-studied in TRICC, such as patients with acute myocardial infarction, traumatic brain injury, or active hemorrhage?
Future Directions: Research continues to refine transfusion thresholds for specific patient populations and to investigate the impact of the age of stored blood on patient outcomes.

14. External Links

Original Article: A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care

15. Framework for Critical Appraisal

Clinical Question: The question was of fundamental importance, challenging a deeply ingrained and resource-intensive standard of care.
Methods: The large, multicenter, randomized design was methodologically strong and provided a high level of evidence.
Results: This is a classic example of a trial where a “non-inferior” or neutral primary outcome was practice-changing. The finding that a restrictive strategy was “at least as effective” as a liberal one, combined with the significant reduction in blood use and signals of benefit in secondary outcomes and subgroups, provided a compelling reason to change practice.
Conclusions and Applicability: The authors’ conclusion is a precise and fair interpretation of the data. The results are highly applicable to the vast majority of ICU patients and have become the foundation of modern transfusion guidelines worldwide.

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.