After univariate and bivariate analyses, multiple regression analysis was performed in a stepwise manner. Model development steps for all transplant recipients and for only those who survived >30 days after transplant are shown in the Supplemental Digital Content, Supplemental Digital Content Tables 1 and 2 (http://links.lww.com/AA/B381). Multiple regression analysis (Table 6) revealed age, year of transplant group, preoperative ventilator support, and prolonged postoperative ventilatory or vasoactive support to be significant confounding variables for log LOS. Multiple regression analysis showed that the occurrence of one or more postoperative major adverse events was not a significant predictor of LOS in the presence of the other covariates; thus, major adverse events were excluded from the final model (Supplemental Digital Content, http://links.lww.com/AA/B381). Age and weight had a direct linear correlation (r = 0.8157; P < 0.0001), and therefore, only age was used. After adjusting for all identified confounding variables, volume of RBC transfusion was not significantly associated with log-transformed LOS (−0.126; −0.274 to 0.022; P = 0.098). Increased age at transplant was associated with a reduction in LOS (−0.093; −0.157 to 0.0289; P = 0.0053), whereas increased duration of postoperative ventilation was associated with longer LOS (0.261; 0.184–0.338; P < 0.0001). Similarly, multiple regression analysis of only those who survived >30 days after transplant showed that RBC transfusion volume had no effect on LOS when confounding variables are considered (Table 7). The 30-day postoperative mortality was 8.87% (25 cases), thus limiting logistic regression analyses to univariate and bivariate models. Univariate and bivariate logistic regression modeling of variables related to 30-day mortality are shown in Tables 8 and 9.
RBC transfusion is a medical intervention in which the risks and benefits must be carefully weighed. Noninfectious risks account for the majority of fatal transfusion complications; most pediatric reports are associated with human errors, such as overtransfusion and misunderstanding neonatal requirements.22 Withholding transfusion may be equally dangerous, because a significant portion of intraoperative pediatric cardiac arrests is associated with inadequate resuscitation of surgical bleeding.23 We found no positive correlation between intraoperative RBC transfusion volume and increased LOS by univariate analysis or multiple regression analysis (−0.126; −0.274 to 0.022; P = 0.098). Univariate analysis showed that infants with delayed chest closure or reoperation for other surgical reasons had larger intraoperative RBC transfusion volumes at the time of transplant, but we did not find significant intraoperative RBC transfusion volume differences in infants who required prolonged postoperative ventilator or vasopressor support or in those who developed new seizures postoperatively, new need for dialysis, cardiac arrest, or death within 30 days of transplant (Tables 2 and 3). Furthermore, multiple regression analysis showed that postoperative major adverse events were not a significant predictor of LOS in the presence of the other covariates (Supplemental Digital Content, http://links.lww.com/AA/B381). Our findings differ from a previous report.5 Several factors may have contributed to this difference.
Infants ≤30 days of age are at greatest risk for blood loss during pediatric cardiac surgery, with blood loss varying inversely with age and notable differences between age groups.24 Although the CPB perfusion strategy in this study was different (hemodilution with large volume acellular prime, followed by hemoconcentration during rewarming though continuous ultrafiltration and concurrent RBC transfusion), the median transfusion volume we found (109 mL/kg) was not significantly greater than that reported in infants <12 months of age in a prior report (95 ± 53 mL/kg).5 That group reported RBC transfusion volume, but not age, to be independently associated with the studied outcomes. They also found that major adverse events (new dialysis, sepsis, graft failure, extracorporeal membrane oxygenation, and open chest) were associated with larger transfusion volumes. In contrast, we found that patient age and weight were directly linked and were independent predictors of LOS, whereas RBC transfusion volume was not. Younger, smaller infants had longer LOS and prolonged vasoactive and ventilator support, possibly reflecting organ system maturation during the first year of life. The outcome differences between studies may highlight a sampling bias: our analysis was restricted to infants up to 12 months of age (median age 50 days), whereas the prior report5 included pediatric cardiac transplant recipients ≤18 years of age (median age 11.7 years). Not surprisingly, infants in that report received the largest blood transfusion volume in milliliters per kilograms; only those weighing >30 kg averaged transfusion volumes <15 mL/kg, placing the majority of transplant recipients <30 kg in the high-exposure group. Although age was not shown to be statistically significant in that report, it had obvious clinical significance; this discrepancy was likely attributable to age differences because only a small number of infants and small children were included in that report. Furthermore, we did not find relationships between transfused volume and several postoperative major adverse events, prolonged postoperative ventilatory or vasoactive support, or death within 30 days of transplant. We postulate that the infant’s immature immune system16–18 and transfusion of washed irradiated RBCs may not elicit the same inflammatory and immunomodulatory effects seen with transfusions to older children and adults, but this will require further investigation.
Previous investigators found that increased transfusion during CPB was associated with excessive postoperative bleeding and worsened outcomes after pediatric cardiac surgery.25 Those investigators reported notable risk factors for excessive postoperative bleeding, which included age and weight. Those with excessive bleeding averaged an age of 138 days and a weight of 5.3 kg compared with an age of 657 days and weight of 10.3 kg in those without excessive bleeding.25 Similarly, infants that required intraoperative and postoperative transfusions despite undergoing a blood-sparing approach to pediatric cardiac surgery had worsened outcomes (increased ventilator days and ICU LOS) compared with nontransfused infants.26,27 However, considering the uniform intraoperative transfusion protocol and maximal blood-sparing approach (including miniaturized CPB circuit down to 95-mL priming volume), it is possible that the need for RBC transfusion is a marker for, rather than the cause of, patient morbidity. Another retrospective study of infants undergoing heart surgery reported that a comprehensive blood conservation strategy, including reduction of circuit priming volume from 600 to 300 mL, was associated with significant decreases in intraoperative and postoperative blood transfusion, inotropic scores, ventilator duration, and hospital LOS (despite lower hemoglobin values after implementation).28 However, it is possible that the other improvements in CPB and patient management implemented in this study contributed favorably to those outcome differences.
Many retrospective studies have linked increased blood transfusions with worsened outcomes. Perhaps the underlying association is the severity of surgical bleeding and preoperative morbidity rather than the amount of blood transfused,29 because 1 study found the volume of chest tube drainage at 24 hours to be the strongest independent predictor of mortality.30 Underlying confounders are difficult to tease out in these retrospective studies. All-cause mortality and secondary outcomes (stroke, myocardial infarction, acute renal failure, infections, arrhythmias, bleeding, ICU, and hospital LOS) were evaluated in a meta-analysis of 21 prospective randomized controlled trials involving transfusion protocols during cardiac or vascular surgery, which randomized to either a restrictive or liberal transfusion study arm (including studies using acute normovolemic hemodilution as a restrictive approach). Four of the studies involved pediatric patients.31 Pediatric patients in the restrictive study arms used significantly less blood, but there were no statistically significant differences in mortality or secondary outcomes. Of note, both ICU and hospital LOS were increased by 1 day in the pediatric patients randomly assigned to a restrictive approach. This meta-analysis also reported numerically more adverse events (death, stroke, and infections) in the restrictive group.31 A review of the literature searching for prospective studies involving RBC transfusion management during surgery for the repair of congenital heart disease in the pediatric population found only a small number of heterogeneous trials with insufficient evidence to assess the outcome impact of RBC transfusions in this subgroup.32
The lowest “safe” hematocrit during CPB has yet to be determined, and there is some evidence that intraoperative anemia may be associated with negative outcomes. A randomized trial in infants <9 months of age to assess the effect of hemodilution (goal hematocrit 20% vs 30%) before low-flow CPB during cardiac surgery found that during the postoperative period the low hematocrit group had decreased cardiac index, higher serum lactate levels, and increased total body water, with no difference in total blood product exposure. Those evaluated in the low hematocrit group at 1 year of age demonstrated >0.5 SD lower Psychomotor Development Index scores.33 The same group of investigators combined these results with a similar study evaluating the difference between hematocrit of 25% vs 35%, which demonstrated that decreased hematocrit before low-flow CPB was associated with increased intraoperative fluid balance and a slight increase in lactate levels 60 minutes after CPB. More importantly, there was a significant nonlinear increase in Psychomotor Development Index scores at 1 year of age with increasing hematocrit (plateauing at hematocrit of 23.5%), raising concern regarding the practice of extreme hemodilution to minimize blood transfusion in infant cardiac surgery.34,35
Our analysis showed that age and weight significantly correlate with LOS. This demonstrates the importance of comparing the outcome impact of RBC transfusion within specific age groups to minimize sampling bias. Additional studies are needed to address the effects of blood transfusion strategies in varied pediatric subgroups, because age and size are linked to estimated blood volume, the resultant dilutional effect of CPB circuit prime, and the amount of physiologic reserve. Infants are more likely to have cyanotic heart disease, require more complex repairs, and have longer duration of CPB and cross-clamp times, which results in increased nonhemostatic thrombin generation, fibrin degradation, and subsequent increased bleeding.36
Weaknesses of this study include its retrospective design over an extended period during which changes have occurred in the approach to infant heart transplantation, blood product storage, and hospital discharge criteria. We have addressed this by evaluating outcomes based on the year of transplant and before-and-after implementation of selective cerebral perfusion during CPB. However, it is possible that other confounding variables remain unaccounted for in this study. There were transfusion guidelines that specified a target postoperative hemoglobin, and the postoperative hemoglobin was within the target range on average. However, this target range was not met in all patients. Washed irradiated RBCs were used per protocol, so there was no control group to evaluate whether this practice affected outcomes. Both lactate and potassium levels rise during blood storage, and the standard protocol for RBC transfusion in transplant recipients involves irradiation, which further weakens the RBC membrane, increasing potassium leakage. Washing irradiated RBCs can reduce potassium and lactate loads, prevent hyperkalemia in infants during CPB, and remove prestorage additives (which may have an unknown effect on the neonate).37–39 This is also an area in need of further research.
There are other limitations to generalizing our findings. Tranexamic acid was not part of the perioperative protocol for infant cardiac transplant, because the risk-benefit ratio in pediatric cardiac surgery had not been adequately established.40 Our study design did not include RBC transfusion or chest tube output during the first 48 hours postoperatively, which could have provided additional pertinent information. The Index for Mortality Prediction After Cardiac Transplantation (IMPACT) score41 was not used, because it was not suitable to distinguish differences within our specific patient population.
Pediatric transfusion medicine is a developing field with large gaps in evidence-based practice.42 Whether increased blood transfusion is the cause of increased morbidity or simply a marker of it remains unclear. Neonates and infants are an important subgroup within the pediatric population requiring unique consideration to account for their maturing organ systems, decreased physiologic reserve, and increased surgical blood loss and RBC transfusion requirement (in mL/kg) compared with their larger counterparts. This retrospective study of RBC transfusion to infants undergoing heart transplantation failed to show a positive correlation between intraoperative RBC transfusion volume and postoperative LOS, while decreased age (which directly correlated with weight) was an independent predictor of increased LOS. The difference in outcomes between this and a prior report5 highlights the possibility of sampling bias in pediatric studies covering a large developmental time period including patients from the first day of life to 18 years of age. Additional prospective studies are needed to determine the outcome impact of RBC transfusion strategies to infants as a unique pediatric subgroup.
The authors express appreciation to those who made significant contributions to this article. Keiji Oda, MA, MPH, assisted with much of the initial statistical analysis. Leonard Bailey, MD, provided insights into this institution’s history and practice of infant heart transplantation including details regarding cardiopulmonary bypass management changes over time. Finally, thanks to James Fitts and the International Heart Institute for sharing from their extensive database.
1. Guzzetta NA. Benefits and risks of red blood cell transfusion in pediatric patients undergoing cardiac surgery. Paediatr Anaesth. 2011;21:504–11
2. Richmond ME, Charette K, Chen JM, Quaegebeur JM, Bacha E. The effect of cardiopulmonary bypass prime volume on the need for blood transfusion after pediatric cardiac surgery. J Thorac Cardiovasc Surg. 2013;145:1058–64
3. Bhaskar B, Dulhunty J, Mullany DV, Fraser JF. Impact of blood product transfusion on short and long-term survival after cardiac surgery: more evidence. Ann Thorac Surg. 2012;94:460–7
4. Costello JM, Graham DA, Morrow DF, Morrow J, Potter-Bynoe G, Sandora TJ, Pigula FA, Laussen PC. Risk factors for surgical site infection after cardiac surgery in children. Ann Thorac Surg. 2010;89:1833–41
5. 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
6. Iyengar A, Scipione CN, Sheth P, Ohye RG, Riegger L, Bove EL, Devaney EJ, Hirsch-Romano JC. Association of complications with blood transfusions in pediatric cardiac surgery patients. Ann Thorac Surg. 2013;96:910–6
7. 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
8. 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
9. 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
10. Székely A, Cserép Z, Sápi E, Breuer T, Nagy CA, Vargha P, Hartyánszky I, Szatmári A, Treszl A. Risks and predictors of blood transfusion in pediatric patients undergoing open heart operations. Ann Thorac Surg. 2009;87:187–97
11. Lacroix J, Hébert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, Gauvin F, Collet JP, Toledano BJ, Robillard P, Joffe A, Biarent D, Meert K, Peters MJTRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators Network. TRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators Network. . Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356:1609–19
12. Willems A, Harrington K, Lacroix J, Biarent D, Joffe AR, Wensley D, Ducruet T, Hébert PC, Tucci MTRIPICU investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. TRIPICU investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. . Comparison of two red-cell transfusion strategies after pediatric cardiac surgery: a subgroup analysis. Crit Care Med. 2010;38:649–56
13. Jacobs JP, Quintessenza JA, Boucek RJ, Morell VO, Botero LM, Badhwar V, van Gelder HM, Asante-Korang A, McCormack J, Daicoff GR. Pediatric cardiac transplantation in children with high panel reactive antibody. Ann Thorac Surg. 2004;78:1703–9
14. Shaddy RE, Fuller TC. The sensitized pediatric heart transplant candidate: causes, consequences, and treatment options. Pediatr Transplant. 2005;9:208–14
15. Dipchand AI, Edwards LB, Kucheryavaya AY, Benden C, Dobbels F, Levvey BJ, Lund LH, Meiser B, Yusen RD, Stehlik JInternational Society of Heart and Lung Transplantation. International Society of Heart and Lung Transplantation. . The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric heart transplantation report–2014; focus theme: retransplantation. J Heart Lung Transplant. 2014;33:985–95
16. Fan X, Ang A, Pollock-Barziv SM, Dipchand AI, Ruiz P, Wilson G, Platt JL, West LJ. Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. Nat Med. 2004;10:1227–33
17. Henderson HT, Canter CE, Mahle WT, Dipchand AI, LaPorte K, Schechtman KB, Zheng J, Asante-Korang A, Singh RK, Kanter KR. ABO-incompatible heart transplantation: analysis of the Pediatric Heart Transplant Study (PHTS) database. J Heart Lung Transplant. 2012;31:173–9
18. West LJ. Defining critical windows in the development of the human immune system. Hum Exp Toxicol. 2002;21:499–505
19. Bailey LLWu Y, Peters MP. Deep hypothermia and total circulatory arrest for cardiac surgery. International Practice in Cardiothoracic Surgery. 1985 Beijing, China Science Press:135–44
20. Razzouk A, Hasaniya N, Bailey LL. Classic single-patch repair of atrioventricular septal defects. Oper Tech Thorac Cardiovasc Surg. 2015;20:75–86
21. Dexter F, Kern FH, Hindman BJ, Greeley WJ. The brain uses mostly dissolved oxygen during profoundly hypothermic cardiopulmonary bypass. Ann Thorac Surg. 1997;63:1725–9
22. Lavoie J. Blood transfusion risks and alternative strategies in pediatric patients. Paediatr Anaesth. 2011;21:14–24
23. Bhananker SM, Ramamoorthy C, Geiduschek JM, Posner KL, Domino KB, Haberkern CM, Campos JS, Morray JP. Anesthesia-related cardiac arrest in children: update from the Pediatric Perioperative Cardiac Arrest Registry. Anesth Analg. 2007;105:344–50
24. Williams GD, Bratton SL, Riley EC, Ramamoorthy C. Association between age and blood loss in children undergoing open heart operations. Ann Thorac Surg. 1998;66:870–5
25. Agarwal HS, Barrett SS, Barry K, Xu M, Saville BR, Donahue BS, Harris ZL, Bichell DP. Association of blood products administration during cardiopulmonary bypass and excessive post-operative bleeding in pediatric cardiac surgery. Pediatr Cardiol. 2015;36:459–67
26. Redlin M, Habazettl H, Boettcher W, Kukucka M, Schoenfeld H, Hetzer R, Huebler M. Effects of a comprehensive blood-sparing approach using body weight-adjusted miniaturized cardiopulmonary bypass circuits on transfusion requirements in pediatric cardiac surgery. J Thorac Cardiovasc Surg. 2012;144:493–9
27. 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
28. Karimi M, Florentino-Pineda I, Weatherred T, Qadeer A, Rosenberg CA, Hudacko A, Ryu D. Blood conservation operations in pediatric cardiac patients: a paradigm shift of blood use. Ann Thorac Surg. 2013;95:962–7
29. 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;117:1175–83
30. Dixon B, Santamaria JD, Reid D, Collins M, Rechnitzer T, Newcomb AE, Nixon I, Yii M, Rosalion A, Campbell DJ. The association of blood transfusion with mortality after cardiac surgery: cause or confounding? (CME). Transfusion. 2013;53:19–27
31. Curley GF, Shehata N, Mazer CD, Hare GM, Friedrich JO. Transfusion triggers for guiding RBC transfusion for cardiovascular surgery: a systematic review and meta-analysis*. Crit Care Med. 2014;42:2611–24
32. Wilkinson KL, Brunskill SJ, Doree C, Trivella M, Gill R, Murphy MF. Red cell transfusion management for patients undergoing cardiac surgery for congenital heart disease. Cochrane Database Syst Rev. 2014;2:CD009752
33. Jonas RA, Wypij D, Roth SJ, Bellinger DC, Visconti KJ, du Plessis AJ, Goodkin H, Laussen PC, Farrell DM, Bartlett J, McGrath E, Rappaport LJ, Bacha EA, Forbess JM, del Nido PJ, Mayer JE Jr, Newburger JW. The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants. J Thorac Cardiovasc Surg. 2003;126:1765–74
34. Newburger JW, Jonas RA, Soul J, Kussman BD, Bellinger DC, Laussen PC, Robertson R, Mayer JE Jr, del Nido PJ, Bacha EA, Forbess JM, Pigula F, Roth SJ, Visconti KJ, du Plessis AJ, Farrell DM, McGrath E, Rappaport LA, Wypij D. Randomized trial of hematocrit 25% versus 35% during hypothermic cardiopulmonary bypass in infant heart surgery. J Thorac Cardiovasc Surg. 2008;135:347–54, 354.e1–4
35. Wypij D, Jonas RA, Bellinger DC, Del Nido PJ, Mayer JE Jr, Bacha EA, Forbess JM, Pigula F, Laussen PC, Newburger JW. The effect of hematocrit during hypothermic cardiopulmonary bypass in infant heart surgery: results from the combined Boston hematocrit trials. J Thorac Cardiovasc Surg. 2008;135:355–60
36. Eisses MJ, Chandler WL. Cardiopulmonary bypass parameters and hemostatic response to cardiopulmonary bypass in infants versus children. J Cardiothorac Vasc Anesth. 2008;22:53–9
37. Cholette JM, Henrichs KF, Alfieris GM, Powers KS, Phipps R, Spinelli SL, Swartz M, Gensini F, Daugherty LE, Nazarian E, Rubenstein JS, Sweeney D, Eaton M, Lerner NB, Blumberg N. Washing red blood cells and platelets transfused in cardiac surgery reduces postoperative inflammation and number of transfusions: results of a prospective, randomized, controlled clinical trial. Pediatr Crit Care Med. 2012;13:290–9
38. Sloan SR. Neonatal transfusion review. Paediatr Anaesth. 2011;21:25–30
39. Swindell CG, Barker TA, McGuirk SP, Jones TJ, Barron DJ, Brawn WJ, Horsburgh A, Willetts RG. Washing of irradiated red blood cells prevents hyperkalaemia during cardiopulmonary bypass in neonates and infants undergoing surgery for complex congenital heart disease. Eur J Cardiothorac Surg. 2007;31:659–64
40. Faraoni D, Willems A, Melot C, De Hert S, Van der Linden P. Efficacy of tranexamic acid in paediatric cardiac surgery: a systematic review and meta-analysis. Eur J Cardiothorac Surg. 2012;42:781–6
41. Kilic A, Allen JG, Arnaoutakis GJ, George TJ, Cameron DE, Vricella LA, Weiss ES. Adult-derived Index for Mortality Prediction After Cardiac Transplantation (IMPACT) risk score predicts short-term mortality after pediatric heart transplantation. Ann Thorac Surg. 2012;93:1228–34
42. Josephson CD, Mondoro TH, Ambruso DR, Sanchez R, Sloan SR, Luban NL, Widness JA. One size will never fit all: the future of research in pediatric transfusion medicine. Pediatr Res. 2014;76:425–31