Highlights
- A large, randomized, multinational trial (2010 patients) evaluated the effectiveness of acute normovolemic hemodilution (ANH) in reducing allogeneic red-cell transfusion during adult cardiac surgery.
- ANH did not significantly reduce the proportion of patients requiring transfusion of allogeneic red cells compared to usual care (27.3% vs. 29.2%, RR 0.93; 95% CI, 0.81–1.07; P=0.34).
- Rates of major complications—including postoperative bleeding, mortality, ischemic events, and acute kidney injury—were similar between groups.
- The findings suggest that routine use of ANH for blood conservation in this setting may not confer additional benefit over standard practice.
Clinical Background and Disease Burden
Cardiac surgery, particularly with the use of cardiopulmonary bypass (CPB), frequently necessitates blood transfusion due to perioperative blood loss and hemodilution. Allogeneic red-cell transfusion, while lifesaving, carries risks such as transfusion reactions, immunomodulation, and infectious complications, and is associated with increased morbidity, mortality, and healthcare costs. As such, blood conservation strategies—including pharmacologic agents, cell salvage, and restrictive transfusion thresholds—are increasingly employed. Acute normovolemic hemodilution (ANH), involving pre-bypass autologous blood withdrawal and subsequent reinfusion, has been advocated as a low-cost, technically straightforward approach, but its efficacy in modern cardiac surgery remains debated, with guideline recommendations based on limited evidence.
Research Methodology
This multinational, single-blind, randomized controlled trial (RCT) enrolled 2010 adults scheduled for cardiac surgery with CPB across 32 centers in 11 countries.
- Interventions: Patients were randomized to either ANH (withdrawal of ≥650 ml of whole blood prior to CPB, replaced with crystalloids as needed, with reinfusion post-bypass) or usual care (no blood withdrawal).
- Primary Endpoint: Receipt of at least one unit of allogeneic red-cell transfusion during the hospitalization.
- Secondary Endpoints: Death from any cause within 30 days or during hospitalization, bleeding complications (including reoperation for bleeding), ischemic complications, and acute kidney injury.
- Statistical Analysis: Relative risk (RR) with 95% confidence intervals (CIs) was calculated for the primary outcome. Safety endpoints and subgroup analyses were also conducted.
Key Findings
A total of 2010 patients were randomized (ANH group n=1010, usual care n=1000). Key results include:
- Allogeneic Red-Cell Transfusion: 27.3% (274/1005) of ANH patients vs. 29.2% (291/997) of usual care patients received at least one unit of allogeneic red cells (RR, 0.93; 95% CI, 0.81–1.07; P=0.34).
- Postoperative Bleeding Reoperation: 3.8% (38/1004) in the ANH group vs. 2.6% (26/995) in the usual care group underwent surgery for bleeding.
- Mortality: Death within 30 days or during hospitalization occurred in 1.4% (14/1008) of ANH patients and 1.6% (16/997) of usual care patients.
- Other Complications: Rates of ischemic events and acute kidney injury were similar between groups.
The absolute difference in transfusion rates was not statistically significant, and secondary safety outcomes were comparable, suggesting that ANH does not substantially alter transfusion requirements or complication risk in the studied population.
Mechanistic Insights and Biological Plausibility
ANH is hypothesized to reduce red-cell loss during surgery by lowering intraoperative hematocrit, thereby decreasing the number of red cells lost in shed blood, and subsequently restoring the patient’s own red cells via reinfusion. However, the magnitude of this effect may be limited by hemodilution during CPB and the effectiveness of modern cell salvage and transfusion guidelines. This trial’s findings suggest that, in contemporary practice, the incremental benefit of ANH is marginal or absent, possibly due to improvements in surgical technique, anesthesia, and transfusion thresholds.
Expert Commentary
Recent guidelines, including those from the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists, have recommended considering ANH as part of a multimodal blood conservation strategy, but acknowledge the paucity of robust RCT evidence. The present study offers high-quality data challenging the routine adoption of ANH in all adult cardiac surgery patients. As Dr. Giovanni Landoni, a co-author, notes, “Our results indicate that ANH, while safe, may not be necessary for all-comers in the current era of blood management.”
Controversies and Limitations
- Generalizability: The trial included diverse international centers, but excluded patients undergoing emergency surgery or those with severe preoperative anemia, potentially limiting applicability to these subgroups.
- Blinding: The trial was single-blind—patients, but not clinicians, were blinded, which could introduce performance bias.
- Protocol Adherence and Variability: The volume of blood withdrawn and reinfused, and perioperative transfusion protocols, may have varied across centers, influencing outcomes.
- Secondary Endpoints: Differences in bleeding reoperation, while numerically higher in the ANH group, were not statistically significant but warrant consideration.
- Concurrent Blood Conservation Strategies: Modern multimodal approaches (cell salvage, antifibrinolytics, restrictive triggers) may have attenuated any potential ANH benefit.
Conclusion
In this large, well-conducted RCT, acute normovolemic hemodilution did not reduce the proportion of patients receiving allogeneic red-cell transfusion during cardiac surgery, nor did it affect major safety outcomes. While ANH remains a safe option, its routine use may not be warranted in centers employing contemporary blood conservation strategies. Future research may focus on high-risk subgroups or alternative blood management algorithms.
References
- Monaco F, Lei C, Bonizzoni MA, Efremov S, Morselli F, Guarracino F, Giardina G, Arangino C, Pontillo D, Vitiello M, Belletti A, et al.; ANH Study Group. A Randomized Trial of Acute Normovolemic Hemodilution in Cardiac Surgery. N Engl J Med. 2025 Jul 31;393(5):450-460. doi: 10.1056/NEJMoa2504948. Epub 2025 Jun 12. PMID: 40503713.
- Society of Thoracic Surgeons, Society of Cardiovascular Anesthesiologists, and American Society of ExtraCorporeal Technology: 2021 Clinical Practice Guidelines on Blood Conservation in Cardiac Surgery. Ann Thorac Surg. 2021;111(5):1398-1414.
- Goodnough LT, Levy JH, Murphy MF. Concepts of blood transfusion in adults. Lancet. 2013;381(9880):1845-1854.