Pediatric Anesthesia 200515: 913–924 doi:10.1111/j.1460-9592.2005.01679.x Review article How to limit allogenic blood transfusion in children B O G U M I L A W O L O S Z C Z U K - G EB I C K A MD Department of Anaesthesiology and Intensive Therapy, The Children’s Memorial Health Institute, Warsaw, Poland Keywords: child; allowable blood loss; blood saving techniques; preoperative autologous blood donation; acute normovolemic hemodilution; cell salvage Introduction In children as in adults, allogenic blood transfusion may be lifesaving, but blood transfusions are accompanied by a number of risks such as blood incompatibilities, transmission of diseases, as well as immunological sensitization with subsequent early and late complications. The decision to transfuse a pediatric patient must be fully justified because the effects of transfusion complications are more longlasting than in adults, whose median age at transfusion may exceed 70 years (1). Parents’ preferences to avoid transfusions or to direct donor blood should also be taken into account when feasible. Another problem is that while blood transfusions have never been safer, the costs of blood products have never been greater. As data evaluating the efficacy of red blood cell (RBC) transfusion are largely lacking, clinical practice guidelines have been based on the opinion of experts who interpreted animal studies and limited human trials. The decision to transfuse should not rest on the hemoglobin concentration alone but must also be based on changes of the physiological parameters such as heart rate, blood pressure, ST-segment changes, mixed venous oxygen saturation, oxygen consumption and lactate concentration in the serum. In addition, the potential for continued blood loss postoperatively must be Correspondence to: Bogumila Woloszczuk-Gebicka, Department of Anaesthesiology and Intensive Therapy, The Children’s Memorial Health Institute, 03-984 Warsaw, Poland (email: gebicka@ czd.waw.pl;
[email protected]). Ó 2005 Blackwell Publishing Ltd factored into the decision to transfuse. Finally, since the safety of blood products varies from country to country in terms of the potential for disease transmission and screening of that blood product, a lower hemoglobin value may be chosen over the marked risk of disease transmission with a transfusion (2). Preparation for surgery The lower the initial hematocrit, the greater the likelihood of blood transfusion in the perioperative period. Therefore, it is logical to start elective surgery with an optimal hematocrit and hemoglobin concentration. Anemia Anemia from iron deficiency is one of the most common alimentary deficits in children. Oral (p.o.) treatment with iron preparations may take months to correct the anemia. Modern intravenous (i.v.) iron preparations seem to be a safe alternative when a rapid reversal of iron deficiency anemia is necessary. The peak response following i.v. iron administration occurs in approximately 10 days. Modern iron preparations, such as sodium ferric gluconate and iron sucrose, are safer than the old ones, especially dextran iron, which may cause anaphyllactoid reactions in susceptible individuals (3). Erythropoietin (human recombinant erythropoietin, rHuEPO ) use in the preoperative period has been approved in the USA since 1997 (4). There are no guidelines for the 913 especially of the brain (9). this decision should be individualized for each patient. which will prevent hyponatremia. 913–924 . Calculate transfusion needs (Table 1.or hypoglycemia.9%) saline and ‘balanced’ crystalloid solutions (lactated Ringer’s) The ion concentration in ‘balanced’ salt solutions is similar to their concentration in plasma. Blood losses occurring intraoperatively should be first replaced with crystalloid solutions (3 ml of crystalloid solution per 1 ml of blood lost) using a balanced salt solution. There are several possible dosing regimes. Tolerated blood loss ¼ volume of blood that the patient can loose before reaching the minimum acceptable hematocrit level. alimentation at a lower rate because giving preoperative volumes may cause hyperglycemia and induce osmotic diuresis. promoting edema. 15. Whatever the preferred choice of i. because such therapy can produce dilutional hyponatremia and hypertonic nonketotic hyperglycemia. Crystalloids: ‘normal’ (0.v. but most anesthesiologists continue to use both. Pediatric Anesthesia.e. Replacement of fluid deficit should always begin with a balanced salt solution to increase the circulating blood volume (8). Patients receiving i.g.v. Blood replacement strategy Step 1. apple juice. ‘Normal’ Ó 2005 Blackwell Publishing Ltd. The ability to increase hemoglobin production in response to erythropoietin may be limited by the iron stores within the body and. allogenic blood or blood products should not be used to maintain the circulating blood volume. or crystalloid-containing solutions given 2–3 h prior to anesthetic induction also reduce thirst and hunger (7).914 B.v. where EBV is estimated blood volume. so it is probably necessary to define therapeutic targets. Intraoperative fluid and blood replacement Children are usually fasted overnight to ensure that the stomach is empty when anesthesia is induced. alimentation must receive some glucose during the surgery to prevent hypoglycemia. Figure 1). especially premature infants. central nervous system compromise or Table 1 Formulae for calculating tolerated blood loss and transfusion needs Tolerated blood loss ¼ EBV · (preoperative Hct – minimum acceptable Hct)/preoperative Hct. e. Intraoperative glucose concentrations must be measured to avoid hyper. Free water containing solutions (i. hemoglobin 13 gÆdl)1.g. clear fluids given 2–3 h before the start of the procedure decrease the volume of gastric contents and increase the pH of the gastric fluid. Expected transfusion needs ¼ expected blood loss – tolerated blood loss uremia. therefore. Therefore. Any significant fluid deficit should be replaced during the first hours of the procedure. on the day of surgery (6). 5% glucose in water) rapidly move out from the vascular compartment and dilute interstitial and cellular compartments. fluid for the treatment of hypovolemia.v. and to achieve them. EBV is related to age. it is recommended to allow unlimited p. 180 IUÆkg)1 rHuEPO per day in the preoperative and early postoperative period (5). e. to get a maximum response we may need to give exogenous iron. this can be achieved either by giving 10% glucose solution during the procedure or by continuing i. or 300 IUÆkg)1 three times per week with daily administration of iron for 3 weeks preoperatively (7). There may be some international differences in the use of crystalloids or colloids. Minimum acceptable hematocrit ¼ minimum Hct level that the patient is expected to tolerate according to the clinical condition. clinical outcome studies suggest that ‘when?’ and ‘how much?’ are probably more important questions than ‘what?’(10). three times a week in the 3 weeks preceding the operation and i. However.o. such as lactated Ringer’s solution. The colloid/crystalloid debate continues to evolve. WOLOSZCZUK-GEBICKA preoperative use of erythropoietin in pediatric patients. intake of clear fluids up to 3 h before the anticipated induction of anesthesia. In children with swallowing difficulties.c. as in adults. 100 IUÆkg)1 s. gastroesophageal reflux. In children. but should be only infused at maintenance rates and not used to make up fluid deficits or to replenish shed blood. Water. Glucose containing solution should be given to young infants. Gelatin solutions Gelatin is a polypeptide made from collagen derived from cattle. Strategy to avoid allogenic blood transfusion. 15. because they have a lower chloride concentration. Pediatric Anesthesia. predonation and/or 2. and the time until first urination was longer with normal saline than with lactated Ringer’s solution (14.9% NaCl subjective mental changes and abdominal discomfort were observed. This is the reason why blood replacement is generally made with a solution such as lactated Ringer’s or normosol. One study suggests that gelatin solutions are less effective than hydroxyethyl starch when used for fluid resuscitation of patients with blunt trauma and increased systemic capillary permeability (16). Hyperchloremic acidosis. as well as some other solutions containing acetate ions are slightly hypotonic. and 154 mmolÆl)1 of chloride. which is much higher than the physiological concentration (98–107 mmolÆl)1). comparable with the plasma expanding effect of crystalloids (Figure 2). which may be a Ó 2005 Blackwell Publishing Ltd. Gelatins are rapidly excreted by the kidneys thereby making their plasma expanding effect short. is not associated with mortality (13). There is mounting evidence that the administration of 0.12). . However. 0.15).H O W T O LI M I T A L L O G E N I C B L O O D T R A N S F U S I O N IN C H I L D R E N 915 Expected blood loss < tolerated blood loss Expected blood loss > tolerated blood loss Proceed with surgery Anemia Normal Hct Consider rescheduling surgery Consider: Possible: give iron with or without erythropoietin Impossible: use allogenic blood transfusion and/or cell saver 1. unlike lactic acidosis. which is comparable with that found is the extracellular space.9% saline and saline-based fluids may cause clinically relevant hyperchloremic acidosis also called strong ions acidosis (11. but it may not be entirely benign. International guidelines mention special requirements for a proper gelatin production process to minimize the risk of transmitting bovine spongiform encephalopathy (BSE). cell saver Figure 1 Step 2. acute normovolemic hemodilution and/or 3. 913–924 matter of concern when dealing with head injury patients. lactated Ringer’s solution. In healthy volunteers which received 50 mlÆkg)1 of 0.9% saline solution contains 154 mmolÆl)1 of sodium.Volume expansion achieved by infusion of gelatins is significantly lower than expansion volume achieved by infusion of albumin or hydroxyethyl starch: only 70–90% of the infused volume. Smaller HES molecules (<70 000 Da) which are a product of HES degradation by a-amylase are eliminated by glomerular filtration.6. hydroxyethyl starch may produce hyperchloremic acidosis (26).v. Large HES molecules are phagocytosed by the reticuloendothelial system.5 700 600 500 400 300 200 100 0 End of infusion 30 min 60 min 90 min Figure 2 Volume effect following an i.916 B.4 amylase. One-hundred ml of 6% solution has a plasma expanding effect of 100–120 ml of whole blood. and itching. and high DS. 200/0. thereby allowing a longer intravascular half-life. but possible. whose physical and chemical characteristics as well as the time course of the volume expanding effect depend on concentration. Hydroxyethyl starch solutions with even smaller particles (70 000 Da) have also been shown to be effective plasma expanders (21). Allergic reactions. It is also safe for patients with head injury (25). The newest HES solution. 33 mlÆkg)1 for 6% HES 200 000/0. mean molecular weight (MW). Autologous blood transfusion Preoperative autologous blood donation.6 glycosidic bonds.4. and 50 mlÆkg)1 for 6% HES 130 000/0. administration of 500 ml of 3. i. for HES 200 000/0.4. hydroxyethyl groups can bind to the C2 or C6 atom of glucose molecule).5. i. and a -1.6 as a plasmavolume expander is an independent risk factor for acute renal failure (22).7. HES 200 000/0.5% gelatin compared with 500 ml of 6% hydroxyethyl starch. The plasma expanding effect of HES 450 000/0. HES preparations have manufacturerrecommended dose limitations to minimize the risk of complications: 20 mlÆkg)1 for 10% HES 200 000/0. and there are no volume limitations.7 is very long (>24 h). up to 140% of infused volume. Native amylopectin can be rapidly cleaved by an endogenous enzyme: a -1.5% gelatin 6% HAES 200/0. Because of possible side effects.4 for adults. Hydroxyethyl starch (HES) Solutions of hydroxyethyl starch in isotonic saline are prepared from corn starch. which consists of branched chains of glucose molecules connected by a-1. 0. Hydroxylation significantly slows down the degradation process. with lower MW and lower DS shows significantly less accumulation and possibly fewer side effects. A 10% solution has more pronounced volume effect.5 used for volume restoration in brain-dead kidney donors has been associated with impaired kidney function in the transplant recipients (23). In patients with severe sepsis or septic shock. coagulation disturbances (17).5. There are several types of hydroxyethyl starch solutions. This rapidly degradable HES solution does not increase the risk for renal dysfunction even when used in large amounts perioperatively (24).e. it lasts approximately 4 h. degree of substitution (DS). As a saline-based solution. and the C2/C6 ratio of substitution (C6/C2. They contain hydroxylated amylopectin.7.e. including volume overload. during intraoperative hemodilution. 15. 450 000 Da. WOLOSZCZUK-GEBICKA 3. Ó 2005 Blackwell Publishing Ltd. and anaphylactoid reactions against animal protein and cross-linking substances are possible (19). the use of hydroxyethyl starch 200 000/0.e. i. and for HES 200 000/0. show significant accumulation and side effects. Pediatric Anesthesia. 6% HES 130 000/0. Preparations with high molecular weight.4 is registered for pediatric use in some European countries. 913–924 . or they undergo hydrolytic cleavage by a-amylase. Anaphylactoid reactions are rare. acute normovolemic hemodilution and cell saving can been successfully used in children. HES 130 000/0.4 glycosidic bonds (20). Similarly. Gelatin solutions are slightly hypooncotic.18).5 and HES 130 000/0. 6 h. gelatins are particularly useful when a short-lasting plasma-expanding effect is needed. They seem to have no adverse effect on coagulation (17. especially coagulation disturbances similar to von Willebrand disease. However. In spite of being stressful. hematocrit. iron supplementation is usually prescribed for the patients participating in a PAD program (37). Children undergoing PAD may donate blood as often as every 4 days.o. PAD has one important advantage over acute normovolemic hemodilution and cell saving: the volume of RBCs really increases during the preoperative period. Blood donation is accompanied by an increase in endogenous erythropoietin levels. VA. until 72 h before surgery. Serial measurements of RBCs. Aggressive phlebotomy (20% of circulating blood volume on two appointments) is well tolerated by generally healthy adolescents preparing for major orthopedic surgery (33). If blood is withdrawn twice weekly. RMI and EPO significantly increase (36). and hemodilution was first reported in children a few years later (39. 913–924 . i. the estimated RBC volume expansion was 220–350 ml of RBC. reticulocyte maturity index (RMI) and endogenous erythropoietin (endogenous EPO) performed throughout the phlebotomy program show that RBC. 12. Available clinical data do not show any advantage of i. though in healthy adults they stay within normal range. reticulocyte count. Hb and serum iron significantly decrease. Reticulocytes.v. iron supplementation over p.75 blood units was produced in excess of basal erythropoiesis (34). whose preparation for surgery needs to be accelerated. the marrow response is often suboptimal and needs adjuvant therapy. administration. and there is no change in serum ferritin levels. Ó 2005 Blackwell Publishing Ltd. Table 2 Blood volume to be withdrawn from children participating in PAD program Body weight (kg) 20–30 30–35 36–42 43–48 >48 Blood volume to be withdrawn (ml) 100 250 325 400 450 American Association of Blood Banks and Transfusion Services.v.40). remain within range of normal. Even very young children can take part in the program. hemoglobin. endogenous erythropoetin response was more substantial. iron administration may be useful in severely malnourished children with very reduced iron stores. Plasma is usually separated from RBCs and frozen immediately to preserve clotting factors. known as iron-deficient erythropoiesis precipitated by PAD. and not always cost-efficient. The suggested blood volume to be withdrawn depends upon body weight (Table 2). and 2–3 units of blood in excess of basal production were produced (in adults) (35). ed. 15. if necessary (31) in spite of the fact that difficult venous access may be a limiting factor. stated that six out of 46 planned PAD could not be performed because of venous access problems or parental apprehension (32). In mild anemia. Mayer.H O W T O LI M I T A L L O G E N I C B L O O D T R A N S F U S I O N IN C H I L D R E N 917 Preoperative autologous blood donation (PAD) Preoperative autologous blood donation is an effective and safe blood saving technique for children and adolescents (27–31). expensive. who reported performing PAD in children as young as 1 year of age. serum ferritin. Hct. 1987. The concept of withdrawing blood and making a patient anemic during surgery to minimize RBC loss and to restore oxygen carrying capacity with the previously withdrawn blood when the major blood loss is over is not new. while significantly higher than the basal level. which. The ability of the patients’ bone marrow to replace the RBC mass reduced by phlebotomies determines the efficacy of PAD. To prevent less efficient. which means that an equivalent to 1–1. serum iron. Pediatric Anesthesia. In adult patients donating 1 unit of blood once a week. First clinical experiences with hemodilution in adults were published in 1974 (38). Acute normovolemic hemodilution (ANH) Acute normovolemic hemodilution is a technique that comprises the removal of whole blood from the patient shortly before the anticipated surgical blood loss and restoring the circulating blood volume with a crystalloid or colloid solution to maintain normal circulating blood volume (‘normovolemia’). Human recombinant erythropoetin may be used to increase further RBC production. However. Arlington. iron-deficient erythropoiesis. 7 gÆdl)1. because the risk of serious neurological complications is great (50). EBV ¼ estimated blood volume ¼ 70 mlÆkg)1 body weight (kg). The efficacy of ANH has also been demonstrated in a well-controlled study during hepatic resection (45. 15. Blood units are retransfused in the reverse order of collection: the first unit collected has the highest hematocrit and the highest concentration of coagulation factors and platelets. 913–924 . ANH will not be very effective. The ‘critical’ hemoglobin concentration is 3. cardiac index increased from 3. The efficacy of acute normovolemic hemodilution can be measured by the red cell mass saved. based on medical status. Hct0 ¼ initial hematocrit Hctf ¼ final hematocrit after blood withdrawal (most often 30%).5 (Ht0 + Htf). Pediatric Anesthesia. In young children. however. Compensatory mechanisms of hemodilution Maintenance of tissue oxygenation during acute normovolemic hemodilution depends on physiological adjustments occurring both in the systemic and the microcirculatory levels. Strict aseptic technique is mandatory both during blood collection and retransfusion. ANH is effective during surgical procedures where blood loss is large and the difference between baseline and target hemoglobin is large (43). The patient must have a high starting hematocrit. unless it is reasonable for the patient to tolerate anemia under anesthesia. If cardiac output can effectively compensate. profound hemodilution should be discouraged. Patient’s blood is collected in standard blood bags containing an anticoagulant. an arterial monitoring line can be used (41). autologous blood can be transfused at the transfusion threshold prior to use of allogenic blood. or when the hematocrit decreases below the value considered safe for the patient (42). coronary arteries are Ó 2005 Blackwell Publishing Ltd.4 lÆmin)1Æm)2 as hematocrit decreased to 16%. A sudden drop in red cell mass lowers blood viscosity and vascular resistance. The efficacy of the mechanism preserving tissue oxygen delivery depends primarily on the maintenance of adequate circulating blood volume. at room temperature to preserve maximum platelet function. Blood is then stored in the operating room. To avoid technical problems with phlebotomy in young children. resulting in an increase in cardiac output and oxygen extraction. Blood must be frequently mixed with the anticoagulant to prevent clot formation in the bag.49).39. At this hematocrit. The trigger hematocrit (‘transfusion threshold’) is determined individually for each patient. volume of the blood to be withdrawn can be calculated as follows: V ¼ EBV Hct0 À Hctf Hcm where V ¼ the volume of blood to be withdrawn.5– 4. (Hct approx. The limits of safe hemodilution The limits for safe hemodilution are unknown. A meta-analysis has confirmed the efficacy of ANH in the population of adult patients undergoing various types of surgery requiring massive transfusion (44). and it does not depend on the type of fluid used for blood replacement.3 lÆmin)1Æm)2 to 4. WOLOSZCZUK-GEBICKA Calculation of the volume of blood to be withdrawn during acute normovolemic hemodilution For practical reasons. as hypovolemia blunts the effects of decreased blood viscosity on venous return. Children seem to be quite resilient when undergoing normovolemic hemodilution (29. Refrigerated blood must be transfused within 24 h. increasing cardiac output. This was associated with a fall is systemic vascular resistance and a rise in stroke volume. but the number of patients reported in the literature is small and we do not know very much about the safety of hemodilution in children at any age. while moderate hemodilution to hematocrit 24–20% during surgery seems safe. and retransfused after major blood loss has ceased. Hctm ¼ mean hematocrit ¼ 0. Oxygen extraction also rose by 50% (47). A scale must be used to accurately quantitate the volume of removed blood.918 B. refrigeration of blood will be necessary. large bore cannula in the internal jugular vein can also be used. 12–14%). O2 delivery to the tissues at the hematocrit of 25–30% is as good as at a hematocrit of 35–45% (48).46). During surgical blood loss. However. and this unit is usually retransfused as the last one. Withdrawn blood is simultaneously replaced with crystalloids (3 ml per 1 ml of blood) or colloid (1 ml per 1 ml of blood). In our own experience. If it is anticipated that more than 6 h will elapse between blood harvest and retransfusion. As predicted by mathematical models. a recent study found a cell saving technique extremely efficient in children with cerebral palsy undergoing acetabuloplasty (59). Unfortunately. Hyperoxic ventilation is a simple.Ædl)1.5 year) studied by Fontana et al. or allow enough time to prepare homologous blood for a trauma victim suffering massive blood loss. For all these reasons. Until recently. it should be kept in mind that this ‘blood’ contains no platelets and no clotting factors. Coagulation disturbances develop not only as a result of the loss of platelets and coagulation factors. keeping in mind that the ‘critical’ hemoglobin concentration is 3. 913–924 . Cell saver produces readily available. but also coagulation disturbances limit safe hemodilution. hypothermia is associated with a leftward shift of the oxyhemoglobin dissociation curve. Nevertheless.53). and packed RBCs in normal saline are returned to the patient. and on the surgeon. Pediatric Anesthesia. However. In the neonate.7 gÆdl)1) has been reported to be safe (52.5 ± 1. When the reservoir is full. no universally accepted definition of anemia requiring transfusion exists. it was estimated that with the use of automated cell-washing devices. In older children (12.2 gÆdl)1 have been reported to be safe (54). normovolemic hemodilution to Hct values of 14–17% (Hb 4. Cell-washing devices can provide the equivalent of up to 10 units of blood per hour to an adult patient with massive bleeding. this limited the use of cell savers in pediatric patients. thus increasing myocardial O2 consumption. However.H O W T O LI M I T A L L O G E N I C B L O O D T R A N S F U S I O N IN C H I L D R E N 919 already maximally dilated and coronary blood flow depends exclusively on the cardiac output (49). ‘Augmented’ intraoperative normovolemic hemodilution Inspired oxygen fraction improves the patient’s tolerance to anemia as the contribution of oxygen dissolved in the plasma increases markedly when the hemoglobin concentration is very low. Cell salvage Cell salvage involves the collection and retransfusion of autologous red cells lost during the perioperative period. we would not recommend dilution to a hemoglobin of below 6 g. however.61). autologous packed RBCs with normal oxygen affinity. but cell salvage alone was not (58). It can reduce allogenic blood exposure and conserve allogenic resources. It may depend on the ability of the surgical team to collect shed blood from the operating field. We can only speculate that this technique is more useful for one type of surgery than for the other.5–4. fresh. Blood coagulation may be further compromised by the potential effect of the plasma expander used. safe and effective intervention for expanding the margin of safety for hemodynamic compensation and tissue oxygenation in hemodiluted subjects experiencing major blood loss (55). It is also impossible to exclude regional hypoxemia. It is especially useful in trauma victims on their way to hospital (56).0 ± 0. who evaluated acute normovolemic hemodilution and cell salvage in adolescent spine fusion surgery stated that ANH was efficient. Ó 2005 Blackwell Publishing Ltd. the margin of safety seems to be very narrow. Copley et al.5 and 9. an equivalent of at least two units of blood needed to be recovered in order for the method to be cost-effective (57). Hemodilution significantly decreases tolerance to cardiovascular depression produced by inhalational anesthetics (51). Moderate hypothermia decreases tissue oxygen demand. and this may depend both on the site and type of surgical procedure. Similarly. as red cells influence normal hemostasis. In otherwise healthy preterm infants hemoglobin concentrations ranging between 5.. the net effect of hypothermia on the critical level of hemodilution is unpredictable. but also anemia itself. and particularly in the premature infants. increasing the hemoglobin affinity for oxygen. hemodilution to Hb 3. The physiological situation in a small infant is different in that O2 demand is already higher at normal Hb and dilutional anemia is compensated by tachycardia. It has an important advantage of being available in an emergency situation. Shed blood is suctioned from the surgical field and collected in a reservoir.7– 5. Therefore.7 gÆdl)1. waste is separated from RBCs.8 gÆdl)1 produced no changes in global oxygen consumption (VO2)(49). cell salvage was found useful in limiting allogenic blood transfusion in infants undergoing surgical correction of craniosynostosis (60. in infants 1–3 years old undergoing noncardiac surgery. 15. increases the amount of oxygen dissolved in plasma and improves the affinity of tissue for oxygen. Not only anemia. there is some evidence in the neonatal study groups that with high-dose aprotinin the inflammatory response is attenuated. who often suffer from complex coagulopathy resulting from consumption of coagulation factors mimicking DIC. orthopedic. as well as during organ transplantations. The efficacy is immediate. Cell salvage also has its limitations. in patients with fat embolism nor when the operating field is contaminated with bacteria or fungi (i.3–0. for the open heart procedures. including acidosis and hypocalcemia.e. holding 70 ml of blood are available for pediatric patients (Cell Saver 5.6%) (65). Recombinant activated factor VII (rFVIIA) Uncontrollable hemorrhage is a major cause of death in trauma victims. which is sometimes impossible to control. This device becomes full with only 40 ml of red cells. It has been recently shown to be an effective method to reduce perioperative blood loss in patients with idiopatic scoliosis (76). this approach can be used as a last resort only. It is not used during the removal of neoplastic tumor. Preliminary results suggest that there is a direct effect of aprotinin on platelet adhesion (71). if there is a potential for bowel perforation. Another extensively studied feature of aprotinin is its anti-inflammatory action. Fibrin glue Fibrin glue is mainly composed of fibrinogen and thrombin plus aprotinin (bovine). and the postoperative course may be better (65). and the reported incidence of anaphylactic reactions to aprotinin is relatively high (0. While no significant influence on the systemic inflammatory response was found in adults during moderate hypothermic cardiopulmonary bypass. Aprotinin also decreased blood transfusion requirements in pediatric patients undergoing craniofacial reconstruction (74). There is no consent concerning its effectiveness in children undergoing primary surgical repair (65. so the red cells can be quickly reinfused to the patient. massive transfusions. and metabolic abnormalities. The effectiveness of aprotinin use in cardiac surgery has been extensively studied. It is thought to act primarily through the inhibition of plasmin. To achieve an adequate plasma concentration. rFVIIA is only Ó 2005 Blackwell Publishing Ltd. It has fewer side effects. aprotinin seems to be significantly more effective (66). The postoperative coagulopathy associated with cardiopulmonary bypass is related to platelet dysfunction. hyperfibrinolysis. At the present time. MA. It reduces allogenic blood transfusion in repeat pediatric open heart surgery (65–67). 913–924 . craniofacial surgery or otolaryngology. hemodilution. USA).920 B. An important advantage of epsilonaminocaproic acid is its low price. hypothermia. complement factors. Other techniques limiting allogenic blood transfusion in children Antifibrinolytic agents Aprotinin and tranexamic acid are used to reduce perioperative bleeding in cardiac. 15. Hemonetics Corp. however. Although the vast majority (>99%) of bacteria can be removed by cell washing and filtering (63).68). which means that it processes less than one-third of the volume required for a standard 225 ml bowl (62). elimination occurs within weeks. interleukins. All these problems lead to severe hemorrhagic diathesis. an abscess. It should also be kept in mind that the use of aprotinin during the primary repair may sensitize the patient. WOLOSZCZUK-GEBICKA Small pediatric bowls. it is considered cost-effective (66. and other blood markers of inflammation (70). Aprotinin may be also beneficial in pediatric lung transplantation (69). the dose must be calculated either by weight or body surface area.. Braintree. Pediatric Anesthesia. but data regarding its efficacy are controversial (75). Both aprotinin and tranexamic acid are also used during liver transplantation (72). The prohemostatic effect of rFVIIa enhances thrombin generation in a tissue-dependent manner. Epsilon aminocaproic acid (tranexamic acid) seems to be more popular in the USA than in Europe. and both components are mixed with calcium chloride immediately before use. in spite of high cost. it must also include an appropriate dose in the prime of the cardiopulmonary bypass circuit (64). it is more likely to hemolyze than if it is collected in a body cavity. If blood is exposed to air on a surface. however. bowel perforation). as assessed by the plasma concentration of the tumor necrosis factor. thrombosis and thromboembolism are a concern in these patients (73).69). There is a linear relationship between O2 partial pressure and the O2 content. Natural hemoglobin interacts strongly with nitric oxide (NO). Fluid therapy can be optimized by using a kinetic model that takes into account the rates of distribution and elimination of the infused fluids. a new model for fluid infusion. as well as the effect of the same replacement fluid in various pathological states (78). There are several phase III clinical trials being conducted on cardiac and orthopedic surgical patients. secondary to its extravasation into the parenchymal tissue. One trial was recently suspended because of the appearance of adverse neurological outcomes (81. named ‘volume kinetics’ has been developed using hemoglobin as a marker for dilution. During the last few years. and therefore they require a high O2 partial pressure in order to carry a sufficient amount of oxygen to achieve clinically important oxygen delivery.H O W T O LI M I T A L L O G E N I C B L O O D T R A N S F U S I O N IN C H I L D R E N 921 approved for use in patients with hemophilia. Perfluorocarbon emulsions (PFC) Perfluorocarbon emulsions are chemically inert carbon–fluoride compounds with no known metabolism. This can be used to compare various replacement fluids. or recombinant systems. a combination of ANH with application of HBOC or PFC during operation. in some countries (i. Pediatric Anesthesia. and this can be used to describe the distribution of fluid to body fluid spaces (which do not always correspond to known anatomical or physiological compartments) (77). The time course of the effect of volume fluid distribution may be investigated by means of computer-assisted simulation. allowing them to carry relatively high amounts of O2 at a relatively low arterial pO2. or by a nomogram based on values for volume kinetics obtained from experiments. There are two classes of these products: hemoglobin-based oxygen carriers (modified hemoglobin solutions and liposome-encapsulated hemoglobin). In contrast with hemoglobin. and has no human or animal origin. Modification of hemoglobin using recombinant technology and site-directed mutagenesis. however.82). evaporative losses and ‘third space’ losses is based on very rough estimates. ‘Augmented normovolemic hemodilution’. Israel) it has been approved for the management of incontrollable bleeding in trauma victims. and perfluorocarbon emulsions. In the future Volume kinetics Evaluation of blood losses. None of them is available for clinical use in Europe or in North America. causes multiple side effects.e. from animals.e. These solutions have a sigmoid O2 dissociation curve. but the hemoglobin glutamer 250 (HBOC-201) has been approved in South Africa (79. Hemoglobin-based oxygen carriers (HBOC) Hemoglobin-based O2 carrier are based on hemoglobin derived from outdated banked human blood. increasing the amount of oxygen physically dissolved in plasma. Pharmacokinetic principles are applied to dilution-time profiles obtained during fluid therapy. 15. has been shown to reduce the need for allogenic blood transfusion in several clinical trials (83–87). none of the artificial oxygen carriers Artificial oxygen carriers Artificial oxygen carriers that can potentially replace RBC transfusion in clinical situations in which banked blood is unavailable or unsafe are in the process of development. the most important of which are pulmonary and systemic vasoconstriction. in combination with some chemical or physical modification (i.80). encapsulation in liposomes). The amount of Ringer’s lactate solution needed to restore a normal circulating blood volume is thought to be 3–5 times the volume of blood lost. They also promote diffusion of oxygen between the RBCs and tissue. which chemically binds oxygen. This interaction. perfluorocarbons carry oxygen as a dissolved gas. 913–924 . None of the clinical trials to this point has been fully successful. Recombinant modified hemoglobin is produced by Eschericha coli Ó 2005 Blackwell Publishing Ltd. They require emulsification since as are not soluble in water. resulted in a series of hemoglobin variants with reduced NO reaction rates and an improved safety profile. Anesth Analg 2003. 15 Reid F. 17: 459–462. Lobo DN. 25 Neff TA. A phase III trial of recombinant human erythropoietin therapy in non-anemic orthopedic patients subjected to aggressive autologous blood phlebotomy: dose. Price TH. Volume replacement with hydroxyethyl starch: is there an influence on kidney function? Anasth Intensivmed Notfallme. A combination of blood saving techniques allowed avoidance of allogenic blood transfusion even during the procedures producing large blood loss. lactated Ringer’s solution. 23 Cittanova ML. Norda R. response. 8 Siker D. Lancet 1996. Ann Roy Coll Surg Eng 2000. Use of erythropoietin for bloodless surgery in a Jehovah’s witness infant. Chasing the base deficit: hyperchloraemic acidosis following 0. J Neurosurg 1998. 15.82. JAMA 2003. Jungheinrich C et al. Anesth Analg 2000. and antifibrinolytic agents (90. (Ab)normal saline and physiological Hartmann’s solution: a randomized doubleblind crossover study. Paediatr Anaesth 2003. 12 Constable PD. Randomized trial of hydroxyethyl starch versus gelatine for trauma resuscitation. 6 Sonzogni V. Paediatr Anaesth 1998. 47: 1114–1121. Liu J. but in adult patients undergoing heart surgery the odds of death with a postoperative hemoglobin <8 gÆdl)1 increases 2. WOLOSZCZUK-GEBICKA developed over the past two decades have been approved for clinical use (except for South Africa). 21 Paul M. or Ringer’s solution on thrombelastograph. 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