In 2013, Howard-Quijano et al.1 reported in Anesthesia & Analgesia that increased intraoperative and postoperative red blood cell (RBC) transfusion was associated with worse clinical outcomes in a cohort of 94 children with a median age of 11.7 years (range, 2 months to 18 years) undergoing heart transplantation. Median perioperative RBC transfusion was 38.7 mL/kg (range, 0–580 mL/kg), and increased transfusion volume was independently associated with increased intensive care unit (ICU) length of stay and higher initial inotrope scores. Transfusions >60 mL/kg were associated with increased risk of major adverse events, including postoperative sepsis, extracorporeal membrane oxygenation, open chest, dialysis, and graft failure. In this issue of Anesthesia & Analgesia, Carter et al.2 report that intraoperative administration of large volumes of RBC transfusion to infants undergoing cardiac transplantation is not associated with increased hospital length of stay or major adverse events. Three hundred seven infants, the majority (66.8%) of whom had single-ventricle physiology, received a median intraoperative RBC transfusion volume of 109 mL/kg (range, 28–328 mL/kg). So what are we going to make of these seemingly contradictory results? Virtually, every patient in both studies was exposed to RBC transfusion so if RBC transfusion volume is the “culprit” associated with adverse outcomes, we would have expected the infants to have fared poorly given their larger transfusion volume burden. Comparison of these studies raises important unanswered, and perhaps unanswerable, questions about the variables that determine the risk–benefit profile of an RBC transfusion in an individual.
Recent evidence suggests that in children undergoing cardiac surgery with cardiopulmonary bypass (CPB), the risk profile for RBC transfusion depends on the indication for the transfusion. In a recent retrospective study, Willems et al.3 compared outcomes in 568 children undergoing cardiac surgery. Three hundred fifty-eight children (median age, 6 months) composed the “CPB-transfusion driven group.” The only RBC transfusion exposure these patients experienced was a RBC transfusion as a part of the CPB prime administered because the calculated hematocrit (HCT) was to be lower than 20% after administration of cardioplegia. Two hundred ten patients (median age, 10 months) composed the “therapeutic” transfusion group. These patients did not receive RBCs as a part of the CPB prime and only received RBC transfusion in the operating room after separation from CPB or in the ICU to treat hemorrhage, to increase oxygen delivery in case of persistent significant right-to-left shunt resulting in a low arterial oxygen saturation (Spo2 <90%), or in case of persistent lactic acidosis or low mixed venous or superior cava saturation after optimization of inotrope administration. RBCs were transfused in the operating room to maintain a HCT >24% or hemoglobin level >8 g/dL. In the ICU, the target HCT was 7 g/dL for noncyanotic and 9 g/dL for cyanotic patients. After multivariate adjustment for other risk factors, the authors found that children exposed to a therapeutic transfusion had significantly higher odds (odds ratio, 2.0; 95% confidence interval [CI], 1.16–3.45) for the composite outcome of severe postoperative morbidity and mortality than children exposed to a transfusion administered during CPB to avoid excessive CPB-induced hemodilution.
The infants in the study by Carter et al.2 were exposed to a CPB prime volume that was extremely large (550 mL) by current standards. This large prime volume virtually guaranteed that RBCs had to be added to the prime solution to avoid excessive hemodilution in infants with a median weight of 3.95 kg. The overwhelming majority (85%) of RBC volume administered to infants in this study was administered during CPB. So, we could consider the majority of the RBC volume exposure to be CPB-driven and not therapeutic. On the contrary, approximately half of the RBC volume administered to patients in the study by Howard-Quijano et al.1 could be considered therapeutic protocol-driven transfusions to “treat patients intra- and postoperatively for a HCT <28%, continued bleeding, or evidence of decreased oxygen-carrying capacity, such as demonstrated by a low mixed venous saturation and/or tachycardia.” The therapeutic RBC transfusions in excess of 60 mL/kg were almost certainly administered in the context of massive blood loss and were associated with an increased risk of composite adverse outcome. Further evidence that RBC transfusion to treat hemorrhage or inadequate systemic oxygen delivery post-CPB as opposed to prevent hemodilution on CPB adversely affects outcome is provided by Redlin et al.4 These authors used a comprehensive blood-sparing technique that largely obviated the need for RBCs in the CPB prime. They used total CPB priming volumes of 95, 110, and 200 mL for infants with a body weight of <3, 3 to 5, and 5 to 16 kg, respectively. The authors demonstrated that intraoperative and postoperative RBC transfusion was associated with prolonged intubation (hazard ratio for early extubation 0.16 [95% CI, 0.09–0.26] and 0.22 [95% CI, 0.14–0.35], respectively). Clearly, we need a much better understanding of how the indication for RBC transfusion and the context of RBC replacement shift the risk–benefit profile for RBC transfusion in children.
Although there is no doubt that RBC transfusion during surgical blood loss is lifesaving and improves outcome in bleeding patients,5 it is doubtful we will ever be able to completely delineate the relative contributions of hemodynamic compromise, inflammation, and the deleterious effects of transfused blood to the adverse outcomes associated with surgical blood loss. A RBC transfusion that does not demonstratively improve system oxygen delivery or replace ongoing blood loss should undergo intense scrutiny. Although our understanding of the consequences and treatment of anemia in adults is becoming more complete and nuanced,6 we currently know very little about the incidence and consequences of perioperative anemia in children. In adult cardiac surgical patients, the combination of anemia and transfusion has been demonstrated to be more deleterious than either entity alone.7 In pediatric cardiac surgical patients, the negative results of the Carter et al. study aside, we should strive to reduce the incidence of CPB-induced anemia through the use of miniaturized CPB circuits. Implementation of multidisciplinary, multimodal patient blood management protocols, designed to optimize RBC mass, minimize blood loss, and optimize physiologic tolerance to anemia, should lead to more rationale utilization of allogeneic blood products.8 In circumstances in which blood loss is inevitable, implementation of preventive strategies and blood loss management algorithms may substantially reduce the volume of allogeneic blood products transfused.9,10
Finally, by way of explanation for the lack of an association between RBC transfusion volume and adverse outcomes, Carter et al. postulate that the infant’s immature immune system and transfusion of washed irradiated RBCs may have mitigated the inflammatory and immunomodulatory effects seen with RBC transfusions in older children and adults. The success of ABO-incompatible heart transplants adds credence to this argument. It is the normal 4- to 8-month delay in isohemagglutinin (antibodies to non-self A and B blood group antigens) development that permits the use of ABO-incompatible grafts in infants.11 Further studies are needed to assess the need to recalibrate our risk-to-benefit assessment for RBC transfusion when we manage infants and neonates compared with older, more immunologically mature children.
Name: James A. DiNardo, MD.
Contribution: This author wrote the editorial.
Attestation: James A. DiNardo wrote the manuscript, reviewed, and approved the final version.
Name: David Faraoni, MD, PhD.
Contribution: This author wrote the editorial.
Attestation: David Faraoni wrote the manuscript and approved the final version.
Dr. James A. DiNardo is the Section Editor for Pediatric Anesthesiology and Pediatric Neuroscience of Anesthesia & Analgesia. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Dinardo was not involved in any way with the editorial process or decision.
1. Howard-Quijano K, Schwarzenberger JC, Scovotti JC, Alejos A, Ngo J, Gornbein J, Mahajan A. Increased red blood cell transfusions are associated with worsening outcomes in pediatric heart transplant patients. Anesth Analg. 2013;116:1295–308.
2. Carter HF, Lau C, Juma D, Wells B, Applegate RL. Intraoperative red blood cell transfusion in infant heart transplant patients is not associated with worsened outcomes. Anesth Analg. 2016;122:1567–77.
3. Willems A, Van Lerberghe C, Gonsette K, De Villé A, Melot C, Hardy JF, Van der Linden P. The indication for perioperative red blood cell transfusions is a predictive risk factor for severe postoperative morbidity and mortality in children undergoing cardiac surgery. Eur J Cardiothorac Surg. 2014;45:1050–7.
4. Redlin M, Kukucka M, Boettcher W, Schoenfeld H, Huebler M, Kuppe H, Habazettl H. Blood transfusion determines postoperative morbidity in pediatric cardiac surgery applying a comprehensive blood-sparing approach. J Thorac Cardiovasc Surg. 2013;146:537–42.
5. DiNardo JA. Blood transfusions might be bad for you; that is unless you are bleeding. Anesth Analg. 2013;116:1201–3.
6. Koch CG. Tolerating anemia: taking aim at the right target before pulling the transfusion trigger. Transfusion. 2014;54:2595–7.
7. Loor G, Rajeswaran J, Li L, Sabik JF III, Blackstone EH, McCrae KR, Koch CG. The least of 3 evils: exposure to red blood cell transfusion, anemia, or both? J Thorac Cardiovasc Surg. 2013;146:1480–1487.e6.
8. Stricker PA, Fiadjoe JE, Kilbaugh TJ, Pruitt EY, Taylor JA, Bartlett SP, McCloskey JJ. Effect of transfusion guidelines on postoperative transfusion in children undergoing craniofacial reconstruction surgery. Pediatr Crit Care Med. 2012;13:e357–62.
9. Romlin BS, Wåhlander H, Berggren H, Synnergren M, Baghaei F, Nilsson K, Jeppsson A. Intraoperative thromboelastometry is associated with reduced transfusion prevalence in pediatric cardiac surgery. Anesth Analg. 2011;112:30–6.
10. Nakayama Y, Nakajima Y, Tanaka KA, Sessler DI, Maeda S, Iida J, Ogawa S, Mizobe T. Thromboelastometry-guided intraoperative haemostatic management reduces bleeding and red cell transfusion after paediatric cardiac surgery. Br J Anaesth. 2015;114:91–102.
11. Irving C, Gennery A, Kirk R. Pushing the boundaries: the current status of ABO-incompatible cardiac transplantation. J Heart Lung Transplant. 2012;31:791–6.