Blood Conservation in Pediatric Cardiac Surgery
Content
TATM 2005;7(1):58-62
Blood Conservation in Pediatric Cardiac Surgery
SUMMARY
There are many blood conservation strategies available for children undergoing cardiac
P HILIPPE P OUARD ,
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surgery. These strategies will vary depending on patient age and type of surgery. The goal of them all, however, is the same, namely to minimize exposure to allogeneic transfusion while maximizing the use of autologous red cells. Every participant in the process, including the cardiologist, anesthesiologist, perfusionist, surgeon, intensivist and laboratory technician, is committed to the overriding objective of blood conservation in pediatric cardiac surgery. Even if the effects and costs of all these methods have not yet been completely assessed, many are available, accurate and need to be implemented.
DEPARTMENTS OF ANESTHESIOLOGY AND PEDIATRIC CARDIAC SURGERY HEAD, CARDIAC ASSISTANCE AND CARDIOPULMONARY BYPASS UNIT HÔPITAL NECKER - ENFANT MALADES PARIS, FRANCE
• Blood conservation • Cardiac surgery • Cardiopulmonary bypass • Children
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Blood conservation has been an ongoing quest since pediatric cardiac surgery (PCS) was in its very infancy. Recent decades have witnessed many improvements in all stages of cardiac surgery, allowing for a move towards bloodless surgery in adult patients1 and even in pediatric patients in some specific fields.2 Moreover, blood transfusion has been associated with an increased mortality rate3 and it remains unclear if it improves survival. Low hematocrit (Hct) during cardiopulmonary bypass (CPB) in adults has been shown to be an independent predictor of operative mortality, prolonged intensive care unit (ICU) stay, postoperative hospital stay and worse 0- to 6-year survival.4 Reports of bloodless surgery in children weighing < 5 kg are rare and do not include trials or studies. Since a great deal of pediatric cardiac surgery is performed during the neonatal period, homologous blood components are essential and blood conservation is a main concern. Cardiologists, surgeons, anesthesiologists, perfusionists and intensivists all play an active role in PCS. To successfully achieve blood conservation, they, as key players, must be strongly committed to the same goal, namely to conserve blood. Nevertheless, blood conservation has to be considered within the context of a risk/benefit strategy and not as an ultimate endpoint.
serum lactate levels, increased total body water) was worse in the lower Hct group.13 In addition, lower Hct was associated with adverse developmental outcome. A more recent report seems to confirm these results.14
Blood Conservation Methods
Blood conservation methods are available in the pre- and perioperative period and include both pharmacological and non-pharmacological methods (Table 1).
Table 1.
Blood Conservation Methods in Pediatric Cardiac Surgery A. Preoperative period 1. Autologous blood donation 2. Erythropoietin B. Perioperative period 1. Nonpharmacological methods a. Limited hemodilution b. Low-primed circuits - Remote pump head - Assisted venous return c. Ultrafiltration d. Appropriate venous cannulation e. Retrograde autologous blood priming f. Red cell salvage 2. Pharmacological methods a. Optimalized heparinization b. Controlled protamine neutralization c. Antifibrinolytics d. Fibrin sealant e. Factor VIIa 3. Operative strategy Normothermia?
Rationale for Blood Conservation
The risk of transfusion-transmitted viral infections (HIV, HCV, HBV) is decreasing in developed countries.5 However, bacterial infections, ABO discrepancies and immunization still remain relevant today and justify the search for blood-sparing strategies. Furthermore, in pediatric cardiac surgery, stored blood in the priming solution has been shown to serve as a source of bradykinin, interleukins (IL) and inflammatory reactions leading to adverse effects.6,7 In contrast with adult patients,8 strategies for transfusion therapy in PCS are not clearly established. This situation is compounded by the fact that there still remain risks inherent to transfusion therapy. Although not specifically the topic of this review, hemodilution is of limited value depending on the patient’s age and pathological condition. The clinically acceptable limit of acute normovolemic, normothermic hemodilution in non-cardiac surgery in healthy children may be very low, i.e., hemoglobin (Hb) concentration as low as 4 g/dL, when ventilating with 100% oxygen.9 The corresponding limit post hypothermic CPB is not known for neonates operated on for congenital cardiac diseases. In a study conducted by Han et al. on children approximately 20-months-old and weighing 10 kg, the authors compared bloodless and blood-adjusted priming.10 Their findings indicate a significant reduction in regional cerebral oxygen saturation at the start of CPB and during rewarming (< 60%) with a 16% Hct. In another pediatric study in which the subjects underwent major non-cardiac surgery, isovolemic hemodilution with a 17% Hct preserved global tissue oxygenation.11 Based on an animal study looking at piglets post hypothermic circulatory arrest,12 Shin’oka et al. concluded that extreme hemodilution (Hct < 10%) in CPB may cause inadequate oxygen delivery and that higher Hct with blood prime is associated with improved cerebral recovery. Finally, a randomized trial of 147 children to compare perioperative outcome in two groups undergoing CPB with 21% (n = 74) or 28% Hct (n = 73) showed that immediate outcome (cardiac index,
Preoperative Period
Autologous blood donation (ABD) and erythropoietin therapy can be used only in older children.
Autologous Blood Donation
ABD is generally performed in children older than 5 years and weighing > 20 kg. It can also be performed in the operating room just before surgery where monitoring capabilities exist. Whole volume storage depends on the number of donations and varies from 10 to 40 mL/kg. Cyanotic disease, outflow tract obstruction and cardiac failure constitute absolute contraindications to ABD. ABD is more efficient when used with erythropoietin therapy. Although ABD does not decrease blood loss, it may obviate the need for blood transfusion.15,16
Erythropoietin Therapy
Erythropoietin is routinely used in association with iron supplementation in children undergoing hemodialysis, cancer treatment
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or immunosuppressive therapy. There are only a few published reports of PCS in the medical literature and they deal primarily with bloodless surgery in Jehovah’s witnesses.17 Erythropoietin is administered at a dose of 100 to 150 units subcutaneously (s.c.), three times a week, during the 3 weeks prior to the procedure and, sometimes, intravenously on the day of surgery. In the cases reported, erythropoietin allowed red cell mass to increase and blood transfusion to be avoided.18
surgery.28,29 The main reasons could be the volume of water reinfused with the red cells and the lack of adapted small devices. Ultrafiltration of the residual volume in the pump circuit allows for the reinfusion of red cells and partially activated coagulation components.30 Ultrafiltration (UF). Since the very beginning, UF during CPB has been associated with reduced blood loss,31,32,33,34 fewer blood transfusions,32,35 and an increased hematocrit.30 Initially, UF took place during the rewarming phase of CPB (conventional ultrafiltration). In a 1991 study, Naïk and Elliott modified the technique so that filtration may occur immediately after CPB (modified ultrafiltration [MUF]).31 When a standardized volume of fluid is removed, the effect on blood transfusion is the same as with conventional or modified ultrafiltration.36 In neonatal surgery, UF is particularly important in reducing postoperative total body water. By lowering the level of inflammatory mediators,37,38 UF could also help to reduce coagulopathic responses. Pharmacological Methods Methods to manage blood loss are mainly pharmacological and essentially entail adequate management of anticoagulation and prevention of fibrinolysis. Surface-modifying additives. During CPB, blood contact with foreign surfaces induces activation of several humoral and cell pathways, resulting in a whole body inflammatory reaction and coagulopathic responses, which, in turn, lead to excessive bleeding. Many technologies have tried to modify blood-contacting surfaces by coating the CPB circuit with or without heparin. The results have been very controversial. Horton et al. reported no significant difference in inflammatory response39 whereas Osawa et al. showed a reduction in IL-6 levels with the use of surfacemodifying additives.40 More recently, Jensen reported activation of fibrinolysis to a lesser degree with the use of a fully heparin-coated circuit than with the use of a conventional system in children.41 Heparin/protamine dosing. As a result of hemodilution and consumption, components of the coagulation and fibrinolytic systems decrease during pediatric CPB. Like hemodilution, consumption can be limited by accurate plasma concentrations of heparin.42 The activated coagulation time (ACT) often used during CPB does not account for factors unrelated to heparin activity, including hemodilution, hypothermia and platelet activation. ACT does not allow for accurate heparin monitoring, particularly in small children.43 No preoperative tests have been found to be predictive of bleeding.44 Nevertheless, platelet count and fibrinogen level during CPB correlate with blood loss in children < 8 kg and maximum amplitude of the TEG (thrombelastograph) in children > 8 kg.45,46 Therefore, in the presence of excessive bleeding before or after protamine infusion, ACT is not accurate and coagulation tests have to be performed. When looking at the management of anticoagulation and its reversal during
Retrograde Autologous Blood Priming (RAP)
RAP is performed in a crystalloid preprimed circuit after CPB cannulation from the venous cannula to the arterial line. It is performed without risk of hemodynamic instability in children weighing > 10 kg. RAP limits the use of hemodilution and is safe because CPB is ready to start any time after the connection between the arterial cannula and the tubing. The efficacy of RAP in adult patients is still controversial and has not yet been reported in children.19,20
Perioperative Period
Many methods are available during the perioperative period to reduce blood transfusion. In terms of efficacy, however, they are not all equal. Of course, adequate surgical hemostasis remains of primary importance and is usually achieved. Perioperative methods can be divided into two categories: methods to limit hemodilution and methods to limit blood loss. Methods to limit hemodilution include low-prime circuits,21,22 remote pump head systems,23 vacuum-assisted venous drainage (VAVD),24 red cell salvage and ultrafiltration. Methods to limit blood loss include surfacemodifying additives, optimal heparin/protamine dosing and pharmacologic modulation of coagulation and fibrinolysis. Certain factors such as duration and temperature of CPB, inadequate venous cannulation and delay between pericardial effusion and suction may increase the risk of blood transfusion during CPB.
Nonpharmacological Methods Miniaturized circuits. Small circuits with a remote pump head allow for a reduction in priming volume to 200 to 250 mL in neonates when 3/16” tubing is used. Small circuits and assisted vacuum-assisted venous return (VAVR)25 have made it possible to decrease the priming volume in both piglets22 and in neonates26 to 107 mL and to 190 mL, respectively. Personal experience and observations have shown that in a neonate with a 300 mL blood volume and a 45% Hct, Hct will decrease to 19% if the circuit priming volume is 400 mL with a clear prime; Hct will decrease to 27% if the circuit priming volume is only 200 mL. To restore the Hct to 45% in the first case will require 180 mL of red cells and only 90 mL in the second. This scenario highlights the importance of reducing the volume of the circuit prime solution. VAVD has been a source of gaseous emboli27 and may be dangerous in neonatal surgery. The decision to use this technique in pediatric surgery must be made judiciously. Cell salvage. Reports of cell saver use are more common in pediatric neurological and orthopedic surgery than in cardiac
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pediatric CPB, a huge heterogeneity is observed in terms of the heparin regimen and calculation of initial and additional protamine dose.47 Many pharmacologic agents are available to achieve hemostasis after cardiac surgery. Not all have been well studied. Depending on the agent, the results and the number of patients enrolled are very different. Antifibrinolytics. Over the years, the efficacy of the serine protease inhibitor aprotinin has been controversial, with positive and negative results in children even during DHCA (deep hypothermic circulatory arrest).48,49 Despite some variable results, recent reports have shown a reduction in operative closure time and blood product use,50 a reduction in allogeneic transfusion,51 a reduction in activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation52 with a high-dose aprotinin regimen. In addition, there is some evidence that a high-dose aprotinin regimen may attenuate the inflammatory reaction in neonates when administered at the appropriate dose. Although there is a correlation between weight and aprotinin concentration,53 the weight-based approach to achieve the effective concentration is not sufficient. Age and priming volume have to be considered because of variation of volume of distribution and renal and liver immaturity. With a bolus dose of 60,000 UIK/kg and a continuous infusion of 12,500 UIK/kg/h, the patients studied by Oliver et al. did not attain the target concentration for anti-inflammatory properties.53 The role of aprotinin in blood conservation seems important during complex pediatric CPB, even if the dose regimen is not yet well defined. The incidence of reported anaphylactic reactions ranges from 0.3 to 2.8%.54 While quantification of antiaprotinin IgG may help to identify patients at risk of developing an anaphylactic reaction to aprotinin re-exposure, it is not always clinically relevant. When aprotinin is indicated, the only way to reduce the consequences of an anaphylactic reaction caused by re-exposure is to wait for the arterial cannulation before starting the aprotinin infusion in order to be ready to go on bypass. In the event of re-exposure, the benefits and risks of aprotinin use always have to be considered. A second agent, tranexamic acid, a lysine analog antifibrinolytic, was shown to reduce postoperative blood loss and total transfusion requirements in a prospective double-blind randomized study.55 In cyanotic children, 100 mg/kg in the pump prime and after bypass has been reported to be as effective as highdose aprotinin in reducing blood loss and transfusion requirements.56 With doses ranging from 50 to 100 mg/kg, from one single to three doses, the optimal dose regimen remains unclear.57,58 Another agent, epsilonaminocaproic acid, has been in use for a long time59 with mixed results in reducing blood loss post PCS.60,61 Miscellaneous drugs. Desmopressin (DDAVP), a trigger for factor VII and von Willebrand factor release, has never been demonstrated to be effective in blood conservation post PCS.62 In addition to these pharmacologic therapies to control bleeding post PCS, recombinant activated factor VII (rFVIIa) has been used as rescue therapy in severe uncontrollable hemorrhage.63 Among the various pharmacological agents, fibrin sealant has a special role in complex repair to achieve surgical hemostasis and reduce bleeding.64
Fresh Whole Blood or Stored Blood? At many institutions, fresh whole blood (FWB) has been used for neonatal cardiac surgery to reduce coagulopathic responses and bleeding. To assess this traditional method, Mou et al.65 conducted a randomized double-blind controlled study comparing FWB versus reconstituted blood in the priming of 200 children. The results showed similar blood loss and transfusion requirements. Moreover, the group receiving the reconstituted blood experienced a shorter ICU stay and a smaller fluid balance at 48 hours. This report reinforces the previous findings of Keidan et al.66 demonstrating that old stored packed red cells have minimal effect in children undergoing cardiac surgery. Strategies to limit allogeneic blood exposure have to consider factors statistically associated with blood loss and blood transfusion. Within this context, Williams et al., in a prospective cohort of 548 children, examined several variables.44 Some, like higher preoperative Hct, lower platelet count during CBP and lower body core temperature, can be manipulated more or less easily. Other factors, such as younger age, longer duration of DHCA, prolonged duration on CPB and resternotomy, are more difficult to manage as regards their surgical usefulness. Weight and duration of CPB have also been demonstrated to be predictive of blood loss.44 CPB technique in neonates may also precipitate the need for blood products if venous cannulation is not totally accurate or if mediastinal blood is not immediately sucked back to the reservoir. Actually, when CPB prime is 200 mL and only 30 mL are missing (in the mediastinum or in the lower part of the body), it will be impossible for the perfusionist to achieve the flow without filling the patient. It is more difficult to specify the accuracy of the transfusion triggers. In clinical practice, there is always a compromise between patient age (neonates need a higher Hct hematocrit and tolerate bleeding less well), complexity of the procedure (suction, hemolysis, time on CPB, non-biological conduits), hemodynamic balance (oxygen delivery, pulmonary vascular resistance, filling pressures), temperature (oxygen demand and viscosity), and the risks of transfusion. In a recent study, Ootaki et al. tried to clarify the efficacy of a criterion-driven transfusion protocol in older children (mean age of 6.2 ± 4.2 years).14 The investigators used body weight, Hct, oxygen venous saturation (SvO2) and postoperative hemodynamic instability as transfusion criteria and found that the transfused patients tended to be younger, smaller and more cyanotic. Transfused patients also had a longer CPB and ischemic time, lower temperature and SvO2. These findings clearly mean that the transfusion criteria depend on the individual case. Unfortunately, there is little in the literature about neonates and infants.
Conclusion
The rising costs of safer blood components and the attendant risks and side effects of blood transfusion justify blood conservation in pediatric cardiac surgery. However, available devices and techniques do not allow for safe bloodless cardiopulmonary bypass for complex repairs in very young and low-weight children. Nor do they allow for realization of the standard mortality rate in PCS, namely between 2 and
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R E F E R E N C E S 1. Ovrum E, Holen EA, Lindstein Ringdal MA. Elective coronary artery bypass surgery without homologous blood transfusion. Early results with an inexpensive blood conservation program. Scand J Thorac Cardiovasc Surg 1991;25:13-8. 2. Gombotz H, Rigler B, Matzer C, Metzler H, Winkler G, Tscheliessnigg KH. [10 years’ experience with heart surgery in Jehovah’s witnesses]. Anaesthesist 1989;38:385-90. 3. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555-62. 4. Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ, Shah A. Adverse effects of low hematocrit during cardiopulmonary bypass in the adult: should current practice be changed? J Thorac Cardiovasc Surg 2003;125:1438-50. 5. Vogt M, Muhlbauer F, Braun SL, et al. Prevalence and risk factors of hepatitis C infection after cardiac surgery in childhood before and after blood donor screening. Infection 2004;32:134-7. 6. Shimpo H, Shimamoto A, Sawamura Y, et al. Ultrafiltration of the priming blood before cardiopulmonary bypass attenuates inflammatory response and improves postoperative clinical course in pediatric patients. Shock 2001;16 Suppl 1:51-4. 7. Nagatsu M, Harada Y, Takeuchi T, Goto H, Kaneko T, Ota Y. [Initial ultrafiltration to the priming solution with preserved blood for cardiopulmonary bypass in infants]. Kyobu Geka 1995;48:281-5. 8. Spahn DR. Strategies for transfusion therapy. Best Pract Res Clin Anaesthesiol 2004;18:661-73. 9. Fontana JL, Welborn L, Mongan PD, Sturm P, Martin G, Bunger R. Oxygen consumption and cardiovascular function in children during profound intraoperative normovolemic hemodilution. Anesth Analg 1995;80:219-25. 10. Han SH, Ham BM, Oh YS, et al. The effect of acute normovolemic haemodilution on cerebral oxygenation. Int J Clin Pract 2004;58:903-6. 11. Aly Hassan A, Lochbuehler H, Frey L, Messmer K. Global tissue oxygenation during normovolaemic haemodilution in young children. Paediatr Anaesth 1997;7:197-204. 12. Shin’oka T, Shum-Tim D, Jonas RA, et al. Higher hematocrit improves cerebral outcome after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 1996;112:1610-20; discussion 1620-1. 13. Jonas RA, Wypij D, Roth SJ, et al. 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. 14. Ootaki Y, Yamaguchi M, Yoshimura N, Oka S, Yoshida M, Hasegawa T. Efficacy of a criterion-driven transfusion protocol in patients having pediatric cardiac surgery. J Thorac Cardiovasc Surg 2004;127:953-8. 15. Masuda M, Kawachi Y, Inaba S, et al. Preoperative autologous blood donations in pediatric cardiac surgery. Ann Thorac Surg 1995;60:1694-7. 16. Masuda H, Moriyama Y, Hisatomi K, et al. Preoperative autologous donation of blood for a simple cardiac anomaly: analysis of children weighing under twenty kilograms. J Thorac Cardiovasc Surg 2000;120:783-9. 17. Alexi-Meskishvili V, Stiller B, Koster A, et al. Correction of congenital heart defects in Jehovah’s Witness children. Thorac Cardiovasc Surg 2004;52:141-6. 18. Shimpo H, Mizumoto T, Onoda K, Yuasa H, Yada I. Erythropoietin in pediatric cardiac surgery: clinical efficacy and effective dose. Chest 1997;111:1565-70. 19. Rosengart TK, DeBois W, O’Hara M, et al. Retrograde autologous priming for cardiopulmonary bypass: a safe and effective means of decreasing hemodilution and transfusion requirements. J Thorac Cardiovasc Surg 1998;115:426-38; discussion 438-9. 20. Murphy GS, Szokol JW, Nitsun M, et al. The failure of retrograde autologous priming of the cardiopulmonary bypass circuit to reduce blood use after cardiac surgical procedures. Anesth Analg 2004;98:1201-7. 21. Shapira OM, Aldea GS, Treanor PR, et al. Reduction of allogeneic blood transfusions after open heart operations by lowering cardiopulmonary bypass prime volume. Ann Thorac Surg 1998;65:724-30. 22. Lau CL, Posther KE, Stephenson GR, et al. Mini-circuit cardiopulmonary bypass with vacuum assisted venous drainage: feasibility of an asanguineous prime in the neonate. Perfusion 1999;14:389-96. 23. Ando M, Takahashi Y, Suzuki N. Open heart surgery for small children without homologous blood transfusion by using remote pump head system. Ann Thorac Surg 2004;78:1717-22. 24. Nakanishi K, Shichijo T, Shinkawa Y, et al. Usefulness of vacuumassisted cardiopulmonary bypass circuit for pediatric open-heart surgery in reducing homologous blood transfusion. Eur J Cardiothorac Surg 2001;20:233-8. 25. Berryessa R, Wiencek R, Jacobson J, Hollingshead D, Farmer K, Cahill G. Vacuum-assisted venous return in pediatric cardiopulmonary bypass. Perfusion 2000;15:63-7. 26. Merkle F, Boettcher W, Schulz F, Koster A, Huebler M, Hetzer R. Perfusion technique for nonhaemic cardiopulmonary bypass prime in neonates and infants under 6 kg body weight. Perfusion 2004;19:229-37. 27. Willcox TW, Mitchell SJ, Gorman DF. Venous air in the bypass circuit: a source of arterial line emboli exacerbated by vacuum-assisted drainage. Ann Thorac Surg 1999;68:1285-9. 28. Suess S, Suess O, Brock M. Neurosurgical procedures in Jehovah’s Witnesses: an increased risk? Neurosurgery 2001;49:266-72; discussion 272-3. 29. Copley LA, Richards BS, Safavi FZ, Newton PO. Hemodilution as a method to reduce transfusion requirements in adolescent spine fusion surgery. Spine 1999;24:219-22; discussion 223-4. 30. Friesen RH, Tornabene MA, Coleman SP. Blood conservation during pediatric cardiac surgery: ultrafiltration of the extracorporeal circuit volume after cardiopulmonary bypass. Anesth Analg 1993;77:702-7. 31. Naik SK, Knight A, Elliott M. A prospective randomized study of a modified technique of ultrafiltration during pediatric open-heart surgery. Circulation 1991;84(5 Suppl):III422-31. 32. Koutlas TC, Gaynor JW, Nicolson SC, Steven JM, Wernovsky G, Spray TL. Modified ultrafiltration reduces postoperative morbidity after cavopulmonary connection. Ann Thorac Surg 1997;64:37-42; discussion 43. 33. Journois D, Pouard P, Greeley WJ, Mauriat P, Vouhe P, Safran D. Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery. Effects on hemostasis, cytokines, and complement components. Anesthesiology 1994;81:1181-9; discussion 26A-27A. 34. Journois D, Israel-Biet D, Pouard P, et al. High-volume, zerobalanced hemofiltration to reduce delayed inflammatory response to cardiopulmonary bypass in children. Anesthesiology 1996;85:965-76. 35. Draaisma AM, Hazekamp MG, Frank M, Anes N, Schoof PH, Huysmans HA. Modified ultrafiltration after cardiopulmonary bypass in pediatric cardiac surgery. Ann Thorac Surg 1997;64:521-5. 36. Thompson LD, McElhinney DB, Findlay P, et al. A prospective randomized study comparing volume-standardized modified and conventional ultrafiltration in pediatric cardiac surgery. J Thorac Cardiovasc Surg 2001;122:220-8. 37. Andreasson S, Gothberg S, Berggren H, Bengtsson A, Eriksson E, Risberg B. Hemofiltration modifies complement activation after extracorporeal circulation in infants. Ann Thorac Surg 1993;56:1515-7. 38. Esmon CT. The impact of the inflammatory response on coagulation. Thromb Res 2004;114:321-7. 39. Horton SB, Butt WW, Mullaly RJ, et al. IL-6 and IL-8 levels after cardiopulmonary bypass are not affected by surface coating. Ann Thorac Surg 1999;68:1751-5. 40. Ozawa T, Yoshihara K, Koyama N, Yamazaki S, Takanashi Y. Superior biocompatibility of heparin-bonded circuits in pediatric cardiopulmonary bypass. Jpn J Thorac Cardiovasc Surg 1999;47:592-9. 41. Jensen E, Andreasson S, Bengtsson A, et al. Influence of two different perfusion systems on inflammatory response in pediatric heart surgery. Ann Thorac Surg 2003;75:919-25. 42. Chan AK, Leaker M, Burrows FA, et al. Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemost 1997;77:270-7. 43. Malviya S. Monitoring and management of anticoagulation in children requiring extracorporeal circulation. Semin Thromb Hemost 1997;23:563-7. 44. Williams GD, Bratton SL, Ramamoorthy C. Factors associated with blood loss and blood product transfusions: a multivariate analysis in children after open-heart surgery. Anesth Analg 1999;89:57-64. 45. Williams GD, Bratton SL, Riley EC, Ramamoorthy C. Coagulation tests during cardiopulmonary bypass correlate with blood loss in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1999;13:398-404. 46. Miller BE, Mochizuki T, Levy JH, et al. Predicting and treating coagulopathies after cardiopulmonary bypass in children. Anesth Analg 1997;85:1196-202. 47. Codispoti M, Ludlam CA, Simpson D, Mankad PS. Individualized heparin and protamine management in infants and children undergoing cardiac operations. Ann Thorac Surg 2001;71:922-7; discussion 927-8. 48. D’Errico CC, Shayevitz JR, Martindale SJ, Mosca RS, Bove EL. The efficacy and cost of aprotinin in children undergoing reoperative open heart surgery. Anesth Analg 1996;83:1193-9. 49. Dietrich W, Mossinger H, Spannagl M, et al. Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations. J Thorac Cardiovasc Surg 1993;105:712-20. 50. Costello JM, Backer CL, de Hoyos A, Binns HJ, Mavroudis C. Aprotinin reduces operative closure time and blood product use after pediatric bypass. Ann Thorac Surg 2003;75:1261-6. 51. Diprose P, Herbertson MJ, O’Shaughnessy D, Deakin CD, Gill RS. Reducing allogeneic transfusion in cardiac surgery: a randomized doubleblind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. Br J Anaesth 2005;94:271-8. 52. Mossinger H, Dietrich W, Braun SL, Jochum M, Meisner H, Richter JA. High-dose aprotinin reduces activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation in pediatric cardiac surgery. Ann Thorac Surg 2003;75:430-7. 53. Oliver WC Jr, Fass DN, Nuttall GA, et al. Variability of plasma aprotinin concentrations in pediatric patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2004;127:1670-7. 54. Dietrich W, Spath P, Zuhlsdorf M, et al. Anaphylactic reactions to aprotinin reexposure in cardiac surgery: relation to antiaprotinin immunoglobulin G and E antibodies. Anesthesiology 2001;95:64-71; discussion 5A-6A. 55. Reid RW, Zimmerman AA, Laussen PC, Mayer JE, Gorlin JB, Burrows FA. The efficacy of tranexamic acid versus placebo in decreasing blood loss in pediatric patients undergoing repeat cardiac surgery. Anesth Analg 1997;84:990-6. 56. Bulutcu FS, Ozbek U, Polat B, Yalcin Y, Karaci AR, Bayindir O. Which may be effective to reduce blood loss after cardiac operations in cyanotic children: tranexamic acid, aprotinin or a combination? Paediatr Anaesth 2005;15:41-6. 57. Vacharaksa K, Prakanrattana U, Suksompong S, Chumpathong S. Tranexamic acid as a means of reducing the need for blood and blood component therapy in children undergoing open heart surgery for congenital cyanotic heart disease. J Med Assoc Thai 2002;85 Suppl 3:S904-9. 58. Chauhan S, Das SN, Bisoi A, Kale S, Kiran U. Comparison of epsilon aminocaproic acid and tranexamic acid in pediatric cardiac surgery. J Cardiothorac Vasc Anesth 2004;18:141-3. 59. McClure PD, Izsak J. The use of epsilon-aminocaproic acid to reduce bleeding during cardiac bypass in children with congenital heart disease. Anesthesiology 1974;40:604-8. 60. Rao BH, Saxena N, Chauhan S, Bisoi AK, Venugopal P. Epsilon aminocaproic acid in paediatric cardiac surgery to reduce postoperative blood loss. Indian J Med Res 2000;111:57-61. 61. Williams GD, Bratton SL, Riley EC, Ramamoorthy C. Efficacy of epsilon-aminocaproic acid in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1999;13:304-8. 62. Hackmann T, Naiman SC. Con: desmopressin is not of value in the treatment of post-cardiopulmonary bypass bleeding. J Cardiothorac Vasc Anesth 1991;5:290-3. 63. Egan JR, Lammi A, Schell DN, Gillis J, Nunn GR. Recombinant activated factor VII in paediatric cardiac surgery. Intensive Care Med 2004;30:682-5. 64. Codispoti M, Mankad PS. Significant merits of a fibrin sealant in the presence of coagulopathy following paediatric cardiac surgery: randomised controlled trial. Eur J Cardiothorac Surg 2002;22:200-5. 65. Mou SS, Giroir BP, Molitor-Kirsch EA, et al. Fresh whole blood versus reconstituted blood for pump priming in heart surgery in infants. N Engl J Med 2004;351:1635-44. 66. Keidan I, Amir G, Mandel M, Mishali D. The metabolic effects of fresh versus old stored blood in the priming of cardiopulmonary bypass solution for pediatric patients. J Thorac Cardiovasc Surg 2004;127:949-52. 67. Aylin P, Bottle A, Jarman B, Elliott P. Paediatric cardiac surgical mortality in England after Bristol: descriptive analysis of hospital episode statistics 1991-2002. BMJ 2004;329:825-9. 68. Lindberg L, Olsson AK, Jogi P, Jonmarker C. How common is severe pulmonary hypertension after pediatric cardiac surgery? J Thorac Cardiovasc Surg 2002;123:1155-63.
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SUMMARY
There are many blood conservation strategies available for children undergoing cardiac
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surgery. These strategies will vary depending on patient age and type of surgery. The goal of them all, however, is the same, namely to minimize exposure to allogeneic transfusion while maximizing the use of autologous red cells. Every participant in the process, including the cardiologist, anesthesiologist, perfusionist, surgeon, intensivist and laboratory technician, is committed to the overriding objective of blood conservation in pediatric cardiac surgery. Even if the effects and costs of all these methods have not yet been completely assessed, many are available, accurate and need to be implemented.
DEPARTMENTS OF ANESTHESIOLOGY AND PEDIATRIC CARDIAC SURGERY HEAD, CARDIAC ASSISTANCE AND CARDIOPULMONARY BYPASS UNIT HÔPITAL NECKER - ENFANT MALADES PARIS, FRANCE
• Blood conservation • Cardiac surgery • Cardiopulmonary bypass • Children
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Blood conservation has been an ongoing quest since pediatric cardiac surgery (PCS) was in its very infancy. Recent decades have witnessed many improvements in all stages of cardiac surgery, allowing for a move towards bloodless surgery in adult patients1 and even in pediatric patients in some specific fields.2 Moreover, blood transfusion has been associated with an increased mortality rate3 and it remains unclear if it improves survival. Low hematocrit (Hct) during cardiopulmonary bypass (CPB) in adults has been shown to be an independent predictor of operative mortality, prolonged intensive care unit (ICU) stay, postoperative hospital stay and worse 0- to 6-year survival.4 Reports of bloodless surgery in children weighing < 5 kg are rare and do not include trials or studies. Since a great deal of pediatric cardiac surgery is performed during the neonatal period, homologous blood components are essential and blood conservation is a main concern. Cardiologists, surgeons, anesthesiologists, perfusionists and intensivists all play an active role in PCS. To successfully achieve blood conservation, they, as key players, must be strongly committed to the same goal, namely to conserve blood. Nevertheless, blood conservation has to be considered within the context of a risk/benefit strategy and not as an ultimate endpoint.
serum lactate levels, increased total body water) was worse in the lower Hct group.13 In addition, lower Hct was associated with adverse developmental outcome. A more recent report seems to confirm these results.14
Blood Conservation Methods
Blood conservation methods are available in the pre- and perioperative period and include both pharmacological and non-pharmacological methods (Table 1).
Table 1.
Blood Conservation Methods in Pediatric Cardiac Surgery A. Preoperative period 1. Autologous blood donation 2. Erythropoietin B. Perioperative period 1. Nonpharmacological methods a. Limited hemodilution b. Low-primed circuits - Remote pump head - Assisted venous return c. Ultrafiltration d. Appropriate venous cannulation e. Retrograde autologous blood priming f. Red cell salvage 2. Pharmacological methods a. Optimalized heparinization b. Controlled protamine neutralization c. Antifibrinolytics d. Fibrin sealant e. Factor VIIa 3. Operative strategy Normothermia?
Rationale for Blood Conservation
The risk of transfusion-transmitted viral infections (HIV, HCV, HBV) is decreasing in developed countries.5 However, bacterial infections, ABO discrepancies and immunization still remain relevant today and justify the search for blood-sparing strategies. Furthermore, in pediatric cardiac surgery, stored blood in the priming solution has been shown to serve as a source of bradykinin, interleukins (IL) and inflammatory reactions leading to adverse effects.6,7 In contrast with adult patients,8 strategies for transfusion therapy in PCS are not clearly established. This situation is compounded by the fact that there still remain risks inherent to transfusion therapy. Although not specifically the topic of this review, hemodilution is of limited value depending on the patient’s age and pathological condition. The clinically acceptable limit of acute normovolemic, normothermic hemodilution in non-cardiac surgery in healthy children may be very low, i.e., hemoglobin (Hb) concentration as low as 4 g/dL, when ventilating with 100% oxygen.9 The corresponding limit post hypothermic CPB is not known for neonates operated on for congenital cardiac diseases. In a study conducted by Han et al. on children approximately 20-months-old and weighing 10 kg, the authors compared bloodless and blood-adjusted priming.10 Their findings indicate a significant reduction in regional cerebral oxygen saturation at the start of CPB and during rewarming (< 60%) with a 16% Hct. In another pediatric study in which the subjects underwent major non-cardiac surgery, isovolemic hemodilution with a 17% Hct preserved global tissue oxygenation.11 Based on an animal study looking at piglets post hypothermic circulatory arrest,12 Shin’oka et al. concluded that extreme hemodilution (Hct < 10%) in CPB may cause inadequate oxygen delivery and that higher Hct with blood prime is associated with improved cerebral recovery. Finally, a randomized trial of 147 children to compare perioperative outcome in two groups undergoing CPB with 21% (n = 74) or 28% Hct (n = 73) showed that immediate outcome (cardiac index,
Preoperative Period
Autologous blood donation (ABD) and erythropoietin therapy can be used only in older children.
Autologous Blood Donation
ABD is generally performed in children older than 5 years and weighing > 20 kg. It can also be performed in the operating room just before surgery where monitoring capabilities exist. Whole volume storage depends on the number of donations and varies from 10 to 40 mL/kg. Cyanotic disease, outflow tract obstruction and cardiac failure constitute absolute contraindications to ABD. ABD is more efficient when used with erythropoietin therapy. Although ABD does not decrease blood loss, it may obviate the need for blood transfusion.15,16
Erythropoietin Therapy
Erythropoietin is routinely used in association with iron supplementation in children undergoing hemodialysis, cancer treatment
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or immunosuppressive therapy. There are only a few published reports of PCS in the medical literature and they deal primarily with bloodless surgery in Jehovah’s witnesses.17 Erythropoietin is administered at a dose of 100 to 150 units subcutaneously (s.c.), three times a week, during the 3 weeks prior to the procedure and, sometimes, intravenously on the day of surgery. In the cases reported, erythropoietin allowed red cell mass to increase and blood transfusion to be avoided.18
surgery.28,29 The main reasons could be the volume of water reinfused with the red cells and the lack of adapted small devices. Ultrafiltration of the residual volume in the pump circuit allows for the reinfusion of red cells and partially activated coagulation components.30 Ultrafiltration (UF). Since the very beginning, UF during CPB has been associated with reduced blood loss,31,32,33,34 fewer blood transfusions,32,35 and an increased hematocrit.30 Initially, UF took place during the rewarming phase of CPB (conventional ultrafiltration). In a 1991 study, Naïk and Elliott modified the technique so that filtration may occur immediately after CPB (modified ultrafiltration [MUF]).31 When a standardized volume of fluid is removed, the effect on blood transfusion is the same as with conventional or modified ultrafiltration.36 In neonatal surgery, UF is particularly important in reducing postoperative total body water. By lowering the level of inflammatory mediators,37,38 UF could also help to reduce coagulopathic responses. Pharmacological Methods Methods to manage blood loss are mainly pharmacological and essentially entail adequate management of anticoagulation and prevention of fibrinolysis. Surface-modifying additives. During CPB, blood contact with foreign surfaces induces activation of several humoral and cell pathways, resulting in a whole body inflammatory reaction and coagulopathic responses, which, in turn, lead to excessive bleeding. Many technologies have tried to modify blood-contacting surfaces by coating the CPB circuit with or without heparin. The results have been very controversial. Horton et al. reported no significant difference in inflammatory response39 whereas Osawa et al. showed a reduction in IL-6 levels with the use of surfacemodifying additives.40 More recently, Jensen reported activation of fibrinolysis to a lesser degree with the use of a fully heparin-coated circuit than with the use of a conventional system in children.41 Heparin/protamine dosing. As a result of hemodilution and consumption, components of the coagulation and fibrinolytic systems decrease during pediatric CPB. Like hemodilution, consumption can be limited by accurate plasma concentrations of heparin.42 The activated coagulation time (ACT) often used during CPB does not account for factors unrelated to heparin activity, including hemodilution, hypothermia and platelet activation. ACT does not allow for accurate heparin monitoring, particularly in small children.43 No preoperative tests have been found to be predictive of bleeding.44 Nevertheless, platelet count and fibrinogen level during CPB correlate with blood loss in children < 8 kg and maximum amplitude of the TEG (thrombelastograph) in children > 8 kg.45,46 Therefore, in the presence of excessive bleeding before or after protamine infusion, ACT is not accurate and coagulation tests have to be performed. When looking at the management of anticoagulation and its reversal during
Retrograde Autologous Blood Priming (RAP)
RAP is performed in a crystalloid preprimed circuit after CPB cannulation from the venous cannula to the arterial line. It is performed without risk of hemodynamic instability in children weighing > 10 kg. RAP limits the use of hemodilution and is safe because CPB is ready to start any time after the connection between the arterial cannula and the tubing. The efficacy of RAP in adult patients is still controversial and has not yet been reported in children.19,20
Perioperative Period
Many methods are available during the perioperative period to reduce blood transfusion. In terms of efficacy, however, they are not all equal. Of course, adequate surgical hemostasis remains of primary importance and is usually achieved. Perioperative methods can be divided into two categories: methods to limit hemodilution and methods to limit blood loss. Methods to limit hemodilution include low-prime circuits,21,22 remote pump head systems,23 vacuum-assisted venous drainage (VAVD),24 red cell salvage and ultrafiltration. Methods to limit blood loss include surfacemodifying additives, optimal heparin/protamine dosing and pharmacologic modulation of coagulation and fibrinolysis. Certain factors such as duration and temperature of CPB, inadequate venous cannulation and delay between pericardial effusion and suction may increase the risk of blood transfusion during CPB.
Nonpharmacological Methods Miniaturized circuits. Small circuits with a remote pump head allow for a reduction in priming volume to 200 to 250 mL in neonates when 3/16” tubing is used. Small circuits and assisted vacuum-assisted venous return (VAVR)25 have made it possible to decrease the priming volume in both piglets22 and in neonates26 to 107 mL and to 190 mL, respectively. Personal experience and observations have shown that in a neonate with a 300 mL blood volume and a 45% Hct, Hct will decrease to 19% if the circuit priming volume is 400 mL with a clear prime; Hct will decrease to 27% if the circuit priming volume is only 200 mL. To restore the Hct to 45% in the first case will require 180 mL of red cells and only 90 mL in the second. This scenario highlights the importance of reducing the volume of the circuit prime solution. VAVD has been a source of gaseous emboli27 and may be dangerous in neonatal surgery. The decision to use this technique in pediatric surgery must be made judiciously. Cell salvage. Reports of cell saver use are more common in pediatric neurological and orthopedic surgery than in cardiac
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pediatric CPB, a huge heterogeneity is observed in terms of the heparin regimen and calculation of initial and additional protamine dose.47 Many pharmacologic agents are available to achieve hemostasis after cardiac surgery. Not all have been well studied. Depending on the agent, the results and the number of patients enrolled are very different. Antifibrinolytics. Over the years, the efficacy of the serine protease inhibitor aprotinin has been controversial, with positive and negative results in children even during DHCA (deep hypothermic circulatory arrest).48,49 Despite some variable results, recent reports have shown a reduction in operative closure time and blood product use,50 a reduction in allogeneic transfusion,51 a reduction in activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation52 with a high-dose aprotinin regimen. In addition, there is some evidence that a high-dose aprotinin regimen may attenuate the inflammatory reaction in neonates when administered at the appropriate dose. Although there is a correlation between weight and aprotinin concentration,53 the weight-based approach to achieve the effective concentration is not sufficient. Age and priming volume have to be considered because of variation of volume of distribution and renal and liver immaturity. With a bolus dose of 60,000 UIK/kg and a continuous infusion of 12,500 UIK/kg/h, the patients studied by Oliver et al. did not attain the target concentration for anti-inflammatory properties.53 The role of aprotinin in blood conservation seems important during complex pediatric CPB, even if the dose regimen is not yet well defined. The incidence of reported anaphylactic reactions ranges from 0.3 to 2.8%.54 While quantification of antiaprotinin IgG may help to identify patients at risk of developing an anaphylactic reaction to aprotinin re-exposure, it is not always clinically relevant. When aprotinin is indicated, the only way to reduce the consequences of an anaphylactic reaction caused by re-exposure is to wait for the arterial cannulation before starting the aprotinin infusion in order to be ready to go on bypass. In the event of re-exposure, the benefits and risks of aprotinin use always have to be considered. A second agent, tranexamic acid, a lysine analog antifibrinolytic, was shown to reduce postoperative blood loss and total transfusion requirements in a prospective double-blind randomized study.55 In cyanotic children, 100 mg/kg in the pump prime and after bypass has been reported to be as effective as highdose aprotinin in reducing blood loss and transfusion requirements.56 With doses ranging from 50 to 100 mg/kg, from one single to three doses, the optimal dose regimen remains unclear.57,58 Another agent, epsilonaminocaproic acid, has been in use for a long time59 with mixed results in reducing blood loss post PCS.60,61 Miscellaneous drugs. Desmopressin (DDAVP), a trigger for factor VII and von Willebrand factor release, has never been demonstrated to be effective in blood conservation post PCS.62 In addition to these pharmacologic therapies to control bleeding post PCS, recombinant activated factor VII (rFVIIa) has been used as rescue therapy in severe uncontrollable hemorrhage.63 Among the various pharmacological agents, fibrin sealant has a special role in complex repair to achieve surgical hemostasis and reduce bleeding.64
Fresh Whole Blood or Stored Blood? At many institutions, fresh whole blood (FWB) has been used for neonatal cardiac surgery to reduce coagulopathic responses and bleeding. To assess this traditional method, Mou et al.65 conducted a randomized double-blind controlled study comparing FWB versus reconstituted blood in the priming of 200 children. The results showed similar blood loss and transfusion requirements. Moreover, the group receiving the reconstituted blood experienced a shorter ICU stay and a smaller fluid balance at 48 hours. This report reinforces the previous findings of Keidan et al.66 demonstrating that old stored packed red cells have minimal effect in children undergoing cardiac surgery. Strategies to limit allogeneic blood exposure have to consider factors statistically associated with blood loss and blood transfusion. Within this context, Williams et al., in a prospective cohort of 548 children, examined several variables.44 Some, like higher preoperative Hct, lower platelet count during CBP and lower body core temperature, can be manipulated more or less easily. Other factors, such as younger age, longer duration of DHCA, prolonged duration on CPB and resternotomy, are more difficult to manage as regards their surgical usefulness. Weight and duration of CPB have also been demonstrated to be predictive of blood loss.44 CPB technique in neonates may also precipitate the need for blood products if venous cannulation is not totally accurate or if mediastinal blood is not immediately sucked back to the reservoir. Actually, when CPB prime is 200 mL and only 30 mL are missing (in the mediastinum or in the lower part of the body), it will be impossible for the perfusionist to achieve the flow without filling the patient. It is more difficult to specify the accuracy of the transfusion triggers. In clinical practice, there is always a compromise between patient age (neonates need a higher Hct hematocrit and tolerate bleeding less well), complexity of the procedure (suction, hemolysis, time on CPB, non-biological conduits), hemodynamic balance (oxygen delivery, pulmonary vascular resistance, filling pressures), temperature (oxygen demand and viscosity), and the risks of transfusion. In a recent study, Ootaki et al. tried to clarify the efficacy of a criterion-driven transfusion protocol in older children (mean age of 6.2 ± 4.2 years).14 The investigators used body weight, Hct, oxygen venous saturation (SvO2) and postoperative hemodynamic instability as transfusion criteria and found that the transfused patients tended to be younger, smaller and more cyanotic. Transfused patients also had a longer CPB and ischemic time, lower temperature and SvO2. These findings clearly mean that the transfusion criteria depend on the individual case. Unfortunately, there is little in the literature about neonates and infants.
Conclusion
The rising costs of safer blood components and the attendant risks and side effects of blood transfusion justify blood conservation in pediatric cardiac surgery. However, available devices and techniques do not allow for safe bloodless cardiopulmonary bypass for complex repairs in very young and low-weight children. Nor do they allow for realization of the standard mortality rate in PCS, namely between 2 and
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R E F E R E N C E S 1. Ovrum E, Holen EA, Lindstein Ringdal MA. Elective coronary artery bypass surgery without homologous blood transfusion. Early results with an inexpensive blood conservation program. Scand J Thorac Cardiovasc Surg 1991;25:13-8. 2. Gombotz H, Rigler B, Matzer C, Metzler H, Winkler G, Tscheliessnigg KH. [10 years’ experience with heart surgery in Jehovah’s witnesses]. Anaesthesist 1989;38:385-90. 3. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555-62. 4. Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ, Shah A. Adverse effects of low hematocrit during cardiopulmonary bypass in the adult: should current practice be changed? J Thorac Cardiovasc Surg 2003;125:1438-50. 5. Vogt M, Muhlbauer F, Braun SL, et al. Prevalence and risk factors of hepatitis C infection after cardiac surgery in childhood before and after blood donor screening. Infection 2004;32:134-7. 6. Shimpo H, Shimamoto A, Sawamura Y, et al. Ultrafiltration of the priming blood before cardiopulmonary bypass attenuates inflammatory response and improves postoperative clinical course in pediatric patients. Shock 2001;16 Suppl 1:51-4. 7. Nagatsu M, Harada Y, Takeuchi T, Goto H, Kaneko T, Ota Y. [Initial ultrafiltration to the priming solution with preserved blood for cardiopulmonary bypass in infants]. Kyobu Geka 1995;48:281-5. 8. Spahn DR. Strategies for transfusion therapy. Best Pract Res Clin Anaesthesiol 2004;18:661-73. 9. Fontana JL, Welborn L, Mongan PD, Sturm P, Martin G, Bunger R. Oxygen consumption and cardiovascular function in children during profound intraoperative normovolemic hemodilution. Anesth Analg 1995;80:219-25. 10. Han SH, Ham BM, Oh YS, et al. The effect of acute normovolemic haemodilution on cerebral oxygenation. Int J Clin Pract 2004;58:903-6. 11. Aly Hassan A, Lochbuehler H, Frey L, Messmer K. Global tissue oxygenation during normovolaemic haemodilution in young children. Paediatr Anaesth 1997;7:197-204. 12. Shin’oka T, Shum-Tim D, Jonas RA, et al. Higher hematocrit improves cerebral outcome after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 1996;112:1610-20; discussion 1620-1. 13. Jonas RA, Wypij D, Roth SJ, et al. 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. 14. Ootaki Y, Yamaguchi M, Yoshimura N, Oka S, Yoshida M, Hasegawa T. Efficacy of a criterion-driven transfusion protocol in patients having pediatric cardiac surgery. J Thorac Cardiovasc Surg 2004;127:953-8. 15. Masuda M, Kawachi Y, Inaba S, et al. Preoperative autologous blood donations in pediatric cardiac surgery. Ann Thorac Surg 1995;60:1694-7. 16. Masuda H, Moriyama Y, Hisatomi K, et al. Preoperative autologous donation of blood for a simple cardiac anomaly: analysis of children weighing under twenty kilograms. J Thorac Cardiovasc Surg 2000;120:783-9. 17. Alexi-Meskishvili V, Stiller B, Koster A, et al. Correction of congenital heart defects in Jehovah’s Witness children. Thorac Cardiovasc Surg 2004;52:141-6. 18. Shimpo H, Mizumoto T, Onoda K, Yuasa H, Yada I. Erythropoietin in pediatric cardiac surgery: clinical efficacy and effective dose. Chest 1997;111:1565-70. 19. Rosengart TK, DeBois W, O’Hara M, et al. Retrograde autologous priming for cardiopulmonary bypass: a safe and effective means of decreasing hemodilution and transfusion requirements. J Thorac Cardiovasc Surg 1998;115:426-38; discussion 438-9. 20. Murphy GS, Szokol JW, Nitsun M, et al. The failure of retrograde autologous priming of the cardiopulmonary bypass circuit to reduce blood use after cardiac surgical procedures. Anesth Analg 2004;98:1201-7. 21. Shapira OM, Aldea GS, Treanor PR, et al. Reduction of allogeneic blood transfusions after open heart operations by lowering cardiopulmonary bypass prime volume. Ann Thorac Surg 1998;65:724-30. 22. Lau CL, Posther KE, Stephenson GR, et al. Mini-circuit cardiopulmonary bypass with vacuum assisted venous drainage: feasibility of an asanguineous prime in the neonate. Perfusion 1999;14:389-96. 23. Ando M, Takahashi Y, Suzuki N. Open heart surgery for small children without homologous blood transfusion by using remote pump head system. Ann Thorac Surg 2004;78:1717-22. 24. Nakanishi K, Shichijo T, Shinkawa Y, et al. Usefulness of vacuumassisted cardiopulmonary bypass circuit for pediatric open-heart surgery in reducing homologous blood transfusion. Eur J Cardiothorac Surg 2001;20:233-8. 25. Berryessa R, Wiencek R, Jacobson J, Hollingshead D, Farmer K, Cahill G. Vacuum-assisted venous return in pediatric cardiopulmonary bypass. Perfusion 2000;15:63-7. 26. Merkle F, Boettcher W, Schulz F, Koster A, Huebler M, Hetzer R. Perfusion technique for nonhaemic cardiopulmonary bypass prime in neonates and infants under 6 kg body weight. Perfusion 2004;19:229-37. 27. Willcox TW, Mitchell SJ, Gorman DF. Venous air in the bypass circuit: a source of arterial line emboli exacerbated by vacuum-assisted drainage. Ann Thorac Surg 1999;68:1285-9. 28. Suess S, Suess O, Brock M. Neurosurgical procedures in Jehovah’s Witnesses: an increased risk? Neurosurgery 2001;49:266-72; discussion 272-3. 29. Copley LA, Richards BS, Safavi FZ, Newton PO. Hemodilution as a method to reduce transfusion requirements in adolescent spine fusion surgery. Spine 1999;24:219-22; discussion 223-4. 30. Friesen RH, Tornabene MA, Coleman SP. Blood conservation during pediatric cardiac surgery: ultrafiltration of the extracorporeal circuit volume after cardiopulmonary bypass. Anesth Analg 1993;77:702-7. 31. Naik SK, Knight A, Elliott M. A prospective randomized study of a modified technique of ultrafiltration during pediatric open-heart surgery. Circulation 1991;84(5 Suppl):III422-31. 32. Koutlas TC, Gaynor JW, Nicolson SC, Steven JM, Wernovsky G, Spray TL. Modified ultrafiltration reduces postoperative morbidity after cavopulmonary connection. Ann Thorac Surg 1997;64:37-42; discussion 43. 33. Journois D, Pouard P, Greeley WJ, Mauriat P, Vouhe P, Safran D. Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery. Effects on hemostasis, cytokines, and complement components. Anesthesiology 1994;81:1181-9; discussion 26A-27A. 34. Journois D, Israel-Biet D, Pouard P, et al. High-volume, zerobalanced hemofiltration to reduce delayed inflammatory response to cardiopulmonary bypass in children. Anesthesiology 1996;85:965-76. 35. Draaisma AM, Hazekamp MG, Frank M, Anes N, Schoof PH, Huysmans HA. Modified ultrafiltration after cardiopulmonary bypass in pediatric cardiac surgery. Ann Thorac Surg 1997;64:521-5. 36. Thompson LD, McElhinney DB, Findlay P, et al. A prospective randomized study comparing volume-standardized modified and conventional ultrafiltration in pediatric cardiac surgery. J Thorac Cardiovasc Surg 2001;122:220-8. 37. Andreasson S, Gothberg S, Berggren H, Bengtsson A, Eriksson E, Risberg B. Hemofiltration modifies complement activation after extracorporeal circulation in infants. Ann Thorac Surg 1993;56:1515-7. 38. Esmon CT. The impact of the inflammatory response on coagulation. Thromb Res 2004;114:321-7. 39. Horton SB, Butt WW, Mullaly RJ, et al. IL-6 and IL-8 levels after cardiopulmonary bypass are not affected by surface coating. Ann Thorac Surg 1999;68:1751-5. 40. Ozawa T, Yoshihara K, Koyama N, Yamazaki S, Takanashi Y. Superior biocompatibility of heparin-bonded circuits in pediatric cardiopulmonary bypass. Jpn J Thorac Cardiovasc Surg 1999;47:592-9. 41. Jensen E, Andreasson S, Bengtsson A, et al. Influence of two different perfusion systems on inflammatory response in pediatric heart surgery. Ann Thorac Surg 2003;75:919-25. 42. Chan AK, Leaker M, Burrows FA, et al. Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemost 1997;77:270-7. 43. Malviya S. Monitoring and management of anticoagulation in children requiring extracorporeal circulation. Semin Thromb Hemost 1997;23:563-7. 44. Williams GD, Bratton SL, Ramamoorthy C. Factors associated with blood loss and blood product transfusions: a multivariate analysis in children after open-heart surgery. Anesth Analg 1999;89:57-64. 45. Williams GD, Bratton SL, Riley EC, Ramamoorthy C. Coagulation tests during cardiopulmonary bypass correlate with blood loss in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1999;13:398-404. 46. Miller BE, Mochizuki T, Levy JH, et al. Predicting and treating coagulopathies after cardiopulmonary bypass in children. Anesth Analg 1997;85:1196-202. 47. Codispoti M, Ludlam CA, Simpson D, Mankad PS. Individualized heparin and protamine management in infants and children undergoing cardiac operations. Ann Thorac Surg 2001;71:922-7; discussion 927-8. 48. D’Errico CC, Shayevitz JR, Martindale SJ, Mosca RS, Bove EL. The efficacy and cost of aprotinin in children undergoing reoperative open heart surgery. Anesth Analg 1996;83:1193-9. 49. Dietrich W, Mossinger H, Spannagl M, et al. Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations. J Thorac Cardiovasc Surg 1993;105:712-20. 50. Costello JM, Backer CL, de Hoyos A, Binns HJ, Mavroudis C. Aprotinin reduces operative closure time and blood product use after pediatric bypass. Ann Thorac Surg 2003;75:1261-6. 51. Diprose P, Herbertson MJ, O’Shaughnessy D, Deakin CD, Gill RS. Reducing allogeneic transfusion in cardiac surgery: a randomized doubleblind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. Br J Anaesth 2005;94:271-8. 52. Mossinger H, Dietrich W, Braun SL, Jochum M, Meisner H, Richter JA. High-dose aprotinin reduces activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation in pediatric cardiac surgery. Ann Thorac Surg 2003;75:430-7. 53. Oliver WC Jr, Fass DN, Nuttall GA, et al. Variability of plasma aprotinin concentrations in pediatric patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2004;127:1670-7. 54. Dietrich W, Spath P, Zuhlsdorf M, et al. Anaphylactic reactions to aprotinin reexposure in cardiac surgery: relation to antiaprotinin immunoglobulin G and E antibodies. Anesthesiology 2001;95:64-71; discussion 5A-6A. 55. Reid RW, Zimmerman AA, Laussen PC, Mayer JE, Gorlin JB, Burrows FA. The efficacy of tranexamic acid versus placebo in decreasing blood loss in pediatric patients undergoing repeat cardiac surgery. Anesth Analg 1997;84:990-6. 56. Bulutcu FS, Ozbek U, Polat B, Yalcin Y, Karaci AR, Bayindir O. Which may be effective to reduce blood loss after cardiac operations in cyanotic children: tranexamic acid, aprotinin or a combination? Paediatr Anaesth 2005;15:41-6. 57. Vacharaksa K, Prakanrattana U, Suksompong S, Chumpathong S. Tranexamic acid as a means of reducing the need for blood and blood component therapy in children undergoing open heart surgery for congenital cyanotic heart disease. J Med Assoc Thai 2002;85 Suppl 3:S904-9. 58. Chauhan S, Das SN, Bisoi A, Kale S, Kiran U. Comparison of epsilon aminocaproic acid and tranexamic acid in pediatric cardiac surgery. J Cardiothorac Vasc Anesth 2004;18:141-3. 59. McClure PD, Izsak J. The use of epsilon-aminocaproic acid to reduce bleeding during cardiac bypass in children with congenital heart disease. Anesthesiology 1974;40:604-8. 60. Rao BH, Saxena N, Chauhan S, Bisoi AK, Venugopal P. Epsilon aminocaproic acid in paediatric cardiac surgery to reduce postoperative blood loss. Indian J Med Res 2000;111:57-61. 61. Williams GD, Bratton SL, Riley EC, Ramamoorthy C. Efficacy of epsilon-aminocaproic acid in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1999;13:304-8. 62. Hackmann T, Naiman SC. Con: desmopressin is not of value in the treatment of post-cardiopulmonary bypass bleeding. J Cardiothorac Vasc Anesth 1991;5:290-3. 63. Egan JR, Lammi A, Schell DN, Gillis J, Nunn GR. Recombinant activated factor VII in paediatric cardiac surgery. Intensive Care Med 2004;30:682-5. 64. Codispoti M, Mankad PS. Significant merits of a fibrin sealant in the presence of coagulopathy following paediatric cardiac surgery: randomised controlled trial. Eur J Cardiothorac Surg 2002;22:200-5. 65. Mou SS, Giroir BP, Molitor-Kirsch EA, et al. Fresh whole blood versus reconstituted blood for pump priming in heart surgery in infants. N Engl J Med 2004;351:1635-44. 66. Keidan I, Amir G, Mandel M, Mishali D. The metabolic effects of fresh versus old stored blood in the priming of cardiopulmonary bypass solution for pediatric patients. J Thorac Cardiovasc Surg 2004;127:949-52. 67. Aylin P, Bottle A, Jarman B, Elliott P. Paediatric cardiac surgical mortality in England after Bristol: descriptive analysis of hospital episode statistics 1991-2002. BMJ 2004;329:825-9. 68. Lindberg L, Olsson AK, Jogi P, Jonmarker C. How common is severe pulmonary hypertension after pediatric cardiac surgery? J Thorac Cardiovasc Surg 2002;123:1155-63.
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