As pointed out by Howard-Quijano et al.1 in this month’s issue of Anesthesia & Analgesia, the majority of patients undergoing pediatric cardiac surgery are exposed to packed red blood cell (PRBC) transfusions primarily to increase systemic oxygen delivery and replace operative blood loss. Unfortunately, a body of literature is accumulating in children and adults that suggests exposure to PRBC transfusion is associated with increased morbidity and mortality.2–5 While this association has been successfully challenged on the grounds that observational clinical studies cannot reliably account for or determine all the confounding variables including bias likely to negate the association,6,7 it cannot be ignored. The relationship between PRBC transfusion and adverse clinical outcomes is likely the result of a complex interplay between multiple factors both known and unknown. In addition, we currently have no clear understanding of how the noninfectious consequences of PRBC transfusion, both immune and nonimmune-mediated, contribute in conjunction with host innate and acquired vulnerabilities to the observed adverse clinical outcomes.8
Howard-Quijano et al.1 have investigated the effects of PRBC transfusion volumes on clinical outcomes in a cohort of pediatric heart transplant patients. They are to be commended on their effort. The authors have done an admirable job of conducting a sophisticated statistical analysis on the retrospective dataset available to them. While appropriately acknowledging the inherent limitations of their investigation, they conclude that escalating volumes of transfused PRBC administered on cardiopulmonary bypass (CPB) and in the first 48 hours postoperatively are independently associated with adverse clinical outcomes. This study is an important contribution to the growing body of literature addressing the relationship between PRBC transfusion and clinical outcomes in children. The results must not be taken only at face value however.
Under normal circumstances, the volume of PRBC administered in the setting of surgical blood loss represents approximately 50% of the estimated blood loss.9 Massive blood loss is defined as loss of >1 blood volume within 1 day of surgery.10 In this study, patients suffering a major adverse event had a median PRBC transfusion of 81.9 mL/kg and the optimal receiver operating characteristic analysis threshold for prediction of a major adverse event was a PRBC transfusion volume of 60 mL/kg. Thus, it is apparent that virtually all of the patients who experienced major adverse events in this study suffered what is considered massive blood loss. While the unit of PRBC used to prime the CPB circuit in patients <10 kg can arguably be excluded when considering blood loss, all other transfusions on CPB were administered in response to loss of red cell mass. Given the conservative transfusion triggers used in the authors’ institution, it is unlikely that any substantial volume of PRBC was transfused for anything other than loss of red cell mass. This is important because the association of massive intraoperative blood loss with mortality has been made previously in adult cardiac surgical patients.10 This investigation provides just as strong an association between the volume of PRBC transfusion and major adverse events as it does between intraoperative blood loss and major adverse events. Finally, this investigation offers no insights on the role large-volume transfusion of other allogenic blood products, such as fresh frozen plasma, platelets, and cryoprecipitate, play in the genesis of major adverse events and mortality. It has recently been demonstrated that perioperative transfusion of increasing volumes of fresh frozen plasma and PRBC are independently associated with reduced cumulative 1-year graft and patient survival after pediatric liver transplantation.11
Should we be tempted to limit or withhold PRBC transfusion in the setting of surgical blood loss? Available evidence suggests that this is unwise particularly for patients with limited physiologic reserve undergoing major surgery. Propensity analysis of a large database of high-risk patients (elderly patients undergoing major noncardiac surgery) demonstrated that while 30-day mortality was higher in transfused versus nontransfused patients, a substantial survival benefit (odds ratio 0.60) was present for transfused versus nontransfused patients with an intraoperative hematocrit <24% and in those with a blood loss of 500 to 999 mL regardless of hematocrit.12 Analysis of data from a very large database has also demonstrated that hospitals with higher transfusion rates for high-risk adult patients with significant blood loss (defined as >500 mL) have lower 30-day adjusted mortality.13 For each 10% increase in the rate of intraoperative transfusion for these high-risk patients, there was a 0.7% reduction in adjusted 30-day mortality.
Rather than simply conclude that PRBC transfusions are bad, the pediatric anesthesia community, particularly the cardiac anesthesia community, needs to embrace the concept of patient blood management.14 The mainstays of this approach are to optimize patient RBC mass, minimize blood loss, and optimize physiologic anemia tolerance.15 The wide range of preoperative hematocrits (19.4–63.7) seen in this study cohort demonstrates that we fall far short of optimizing RBC mass before major surgery. Anemia is common in pediatric heart failure patients, and transfusion of leukoreduced PRBC appears to carry a low risk of allosensitization.16,17 Finally, we must work closely with our surgical colleagues and stress the importance of meticulous hemostasis because there is no evidence that multimodal blood conservation techniques can prevent large-volume blood loss.18
It is increasingly clear that the presence of free hemoglobin (fHb) and iron in plasma from red cell hemolysis is detrimental to multiple organ systems.19,20 Oxygenated fHb is an avid scavenger of nitric oxide (NO), reducing NO bioavailability and thereby inducing global microvascular dysfunction and impaired vasodilation. Free heme reacts with hydrogen peroxide to form toxic free radicals causing direct tissue injury. fHb is associated with development of acute renal injury as a result of direct renal tissue damage induced by both urinary and intratubular fHb, formation of tubular luminal obstructive casts, and tubular epithelium injury induced by plasma fHb scavenging of NO with subsequent vasoconstriction.21
Consequently, scavenging of large-volume blood loss with enthusiastic use of cardiotomy suction and transfusion of aged blood during pediatric cardiac surgery both warrant re-examination. Scavenging of NO by fHb is likely to be particularly detrimental to pediatric heart transplant patients who are vulnerable to right ventricular failure and who likely have an elevated and highly reactive pulmonary vascular resistance. Nontransferrin-bound iron released from hemolyzed red cells has been implicated in promoting bacteria proliferation and inflammation.22 The immunosuppressed heart transplantation population would be particularly vulnerable to this effect as well.
This work by Howard-Quijano and colleagues1 should serve to motivate the pediatric anesthesia community to look more critically at the risk/benefit profile of PRBC transfusion. This will not be easy. There is no large patient population with a relatively homogeneous demographic such as adults undergoing coronary artery bypass surgery to study. We need to recognize that transfusion of PRBC to replace blood loss during surgery most certainly has a different risk/benefit profile than transfusion of PRBC in the intensive care unit to improve systemic oxygen delivery or reduce the requirement for vasoactive agent infusions. Certainly the risk/benefit profile will be different for children with single ventricle physiology as compared with 2-ventricle physiology.
Name: James A. DiNardo, MD.
Contribution: The author is solely responsible for the contents of this contribution.
Attestation: James A. DiNardo, MD approved the final manuscript.
This manuscript was handled by: Peter J. Davis, MD.
1. Howard-Quijano K, Schwarzenberger JC, Scovotti J, 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. Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med. 2008;36:2667–74
3. Salvin JW, Scheurer MA, Laussen PC, Wypij D, Polito A, Bacha EA, Pigula FA, McGowan FX, Costello JM, Thiagarajan RR. Blood transfusion after pediatric cardiac surgery is associated with prolonged hospital stay. Ann Thorac Surg. 2011;91:204–10
4. Kipps AK, Wypij D, Thiagarajan RR, Bacha EA, Newburger JW. Blood transfusion is associated with prolonged duration of mechanical ventilation in infants undergoing reparative cardiac surgery. Pediatr Crit Care Med. 2011;12:52–6
5. Kneyber MC, Hersi MI, Twisk JW, Markhorst DG, Plötz FB. Red blood cell transfusion in critically ill children is independently associated with increased mortality. Intensive Care Med. 2007;33:1414–22
6. Karkouti K, Stukel TA, Beattie WS, Elsaadany S, Li P, Berger R, Wijeysundera DN.. Relationship of Erythrocyte Transfusion with Short- and Long-term Mortality in a Population-based Surgical Cohort. Anesthesiology. 2012;117:13–8
7. Glance LG, Dick AW, Mukamel DB, Fleming FJ, Zollo RA, Wissler R, Salloum R, Meredith UW, Osler TM. Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery. Anesthesiology. 2011;114:283–92
8. Lavoie J. Blood transfusion risks and alternative strategies in pediatric patients. Pediatr Anesth. 2010;21:14–24
9. Ho AM, Dion PW, Cheng CA, Karmakar MK, Cheng G, Peng Z, Ng YW. A mathematical model for fresh frozen plasma transfusion strategies during major trauma resuscitation with ongoing hemorrhage. Can J Surg. 2005;48:470–8
10. Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, Ghannam M, Yeo E, Djaiani G, Karski J. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion. 2004;44:1453–62
11. Nacoti M, Cazzaniga S, Lorusso F, Naldi L, Brambillasca P, Benigni A, Corno V, Colledan M, Bonanomi E, Vedovati S, Buoro S, Falanga A, Lussana F, Barbui T, Sonzogni V. The impact of perioperative transfusion of blood products on survival after pediatric liver transplantation. Pediatr Transplant. 2012;16:357–66
12. Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G, Mor V, Sharma SC, Vezeridis M, Khuri SF, Friedmann PD. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg. 2010;252:11–7
13. Wu WC, Trivedi A, Friedmann PD, Henderson WG, Smith TS, Poses RM, Uttley G, Vezeridis M, Eaton CB, Mor V. Association between hospital intraoperative blood transfusion practices for surgical blood loss and hospital surgical mortality rates. Ann Surg. 2012;255:708–14
14. Goodnough LT, Shander A. Patient blood management. Anesthesiology. 2013;116:1367–76
15. Ranucci M, Aronson S, Dietrich W, Dyke CM, Hofmann A, Karkouti K, Levi M, Murphy GJ, Sellke FW, Shore-Lesserson L, von Heymann CEuropean Association of Cardiothoracic Anaesthesiologists. . Patient blood management during cardiac surgery: do we have enough evidence for clinical practice? J Thorac Cardiovasc Surg. 2011;142:249.e1–32
16. Kammache I, Parrinello G, Marini D, Bonnet D, Agnoletti G. Anaemia is a predictor of early death or cardiac transplantation in children with idiopathic dilated cardiomyopathy. CTY. 2012;22:293–300
17. Mahle WT, Berg AM, Kanter KR. Red blood cell transfusions in children awaiting heart transplantation. Pediatr Transplant. 2011;15:728–32
18. Karkouti K, McCluskey SA. Perioperative blood conservation–the experts, the elephants, the clinicians, and the gauntlet. Can J Anaesth. 2007;54:861–7
19. Vermeulen Windsant IC, Hanssen SJ, Buurman WA, Jacobs MJ. Cardiovascular surgery and organ damage: time to reconsider the role of hemolysis. J Thorac Cardiovasc Surg. 2011;142:1–11
20. Hod EA, Spitalnik SL. Stored red blood cell transfusions: Iron, inflammation, immunity, and infection. Transfus Clin Biol. 2012;19:84–9
21. Vermeulen Windsant IC, Snoeijs MG, Hanssen SJ, Altintas S, Heijmans JH, Koeppel TA, Schurink GW, Buurman WA, Jacobs MJ. Hemolysis is associated with acute kidney injury during major aortic surgery. Kidney Int. 2010;77:913–20
22. Hod EA, Brittenham GM, Billote GB, Francis RO, Ginzburg YZ, Hendrickson JE, Jhang J, Schwartz J, Sharma S, Sheth S, Sireci AN, Stephens HL, Stotler BA, Wojczyk BS, Zimring JC, Spitalnik SL. Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non-transferrin-bound iron. Blood. 2011;118:6675–82