Strategies for Blood Product Management and Reducing Transfusions

10 Strategies for Blood Product Management and Reducing Transfusions




DESPITE ADVANCES IN PEDIATRIC SURGERY, the number of infants and children who sustain major operative blood loss remains high. Little information is available about when to expect coagulation defects in the pediatric age group,1,2 and most studies of massive blood transfusion have involved adult patients.3


Judicious blood transfusion is imperative because the supply of blood is limited and because transfusions can cause complications. The risk of these complications varies around the world. In countries with sophisticated health care systems, the most common fatal hazards of transfusion are hemolytic transfusion reactions due to ABO incompatibility (usually as a result of a transfusion error), bacterial infection, or transfusion-related acute lung injury (TRALI). In developing countries, the risk of infectious disease transmission may be substantial because of endemic infections in the population and the technical or logistic limitations of donor screening.


Nothing changed the use of blood products more than the threat of the acquired immunodeficiency syndrome (AIDS).46 Although infection with human immunodeficiency virus (HIV) by blood transfusion has become rare, it was widely publicized in the lay press and is still feared by the public. Implementation of donor education programs, improved health history screening, new tests, and new test technologies (Table 10-1) have markedly altered the spectrum of transfusion-transmitted infectious agents in the developed world. The risks of some of the infectious and noninfectious hazards of transfusion are summarized in Table 10-2.


TABLE 10-1 Current Blood Screening Tests Used on Donated Blood in the United States



*This test depends on the incidence in the geographic area.


As of December 2011, at first donation or after residence in endemic area.


From American Association of Blood Banks. Facts about blood and blood banking, 2006. 509 Available at www.aabb.org/resources/bct/Pages/bloodfaq.aspx (accessed May 2012).


TABLE 10-2 Estimated Frequency of Complications per Number of Units Transfused



































































Category Complication Frequency
Noninfectious Allergic (urticarial) 1 : 100
  Febrile, nonhemolytic 1 : 100
  Transfusion-associated circulatory overload 1 : 1000
  Delayed hemolytic 1 : 1600
  Transfusion-related acute lung injury 1 : 10,000
  Acute hemolytic 1 : 50,000
  Fatal acute hemolytic 1 : 500,000
Infectious Hepatitis B virus 1 : 250,000
  Hepatitis C virus 1 : 1,800,000
  Human T-lymphotropic virus type I 1 : 3,000,000
  Human immunodeficiency virus type 1 1 : 2,300,000
  Bacterial contamination of red blood cells 1 : 50,000
  Bacterial sepsis of red blood cells 1 : 500,000
  Bacterial contamination of platelets 1 : 2,000
  Bacterial sepsis of platelets 1 : 75,000

Data from Davenport RD. Management of transfusion reactions. In: Mintz PD, editor. Transfusion therapy: clinical principles and practice. 3rd ed. Bethesda, Md.: AABB Press; 2011, p. 757-84; Alter HJ, Esteban-Mur JI. Transfusion transmitted hepatitis. In: Simon TL, Snyder EL, Solheim BG, et al., editors. Rossi’s principles of transfusion medicine. 4th ed. Oxford: AABB Press, Wiley-Blackwell; 2009, p. 718-45; Barbara JA, Dow BC. Retroviruses and other viruses. In: Simon TL, Snyder EL, Solheim BG, et al., editors. Rossi’s principles of transfusion medicine. 4th ed. Oxford: AABB Press, Wiley-Blackwell; 2009, p. 746-59; Park YA, Brecher ME. Bacterial contamination of blood products. In: Simon TL, Snyder EL, Solheim BG, et al., editors. Rossi’s principles of transfusion medicine. 4th ed. Oxford: AABB Press, Wiley-Blackwell; 2009, p. 773-90.


Despite marked reductions in the transmission of HIV, hepatitis C virus, and hepatitis B virus, transfusions can produce other deleterious effects.7,8 Every transfusion must be medically justified; benefits must be weighed against the potential infectious, immunologic, and metabolic risks.9 It is in the child’s best interest to transfuse with a clear clinical goal and in the anesthesiologist’s best interest to document the reason for each transfusion. It is not acceptable medical practice to administer a transfusion when it is of questionable benefit.



Blood Volume


The circulating blood volume should be estimated before induction of anesthesia. The blood volume of a preterm infant (90 to 100 mL/kg) constitutes a greater proportion of body weight than that of a term neonate (80 to 90 mL/kg), infants between 3 months and 1 year old (70 to 80 mL/kg), or an older child (70 mL/kg). Consideration must also be given to body habitus. For example, an obese child has a blood volume of 60 to 65 mL/kg. From the estimated blood volume, the initial hemoglobin or hematocrit, and the minimum acceptable hematocrit, an estimation can be made of the maximum allowable blood loss (MABL) before red blood cell (RBC) transfusion is indicated.


The minimum acceptable hematocrit varies according to an individual child’s need. The balance between oxygen supply and demand depends on a number of factors, including the oxygen content of blood, cardiac output and its regional distribution, and metabolic needs. A child with severe pulmonary disease or cyanotic congenital heart disease probably requires a greater hematocrit than a healthy child to satisfy the metabolic oxygen demands. Preterm infants may require a greater hematocrit to prevent apnea, reduce cardiac and respiratory work, and possibly improve neurologic outcomes,10 although a Cochrane review suggests that this may not be the case.11 If there is uncertainty about the need to transfuse these infants, the neonatologist should be consulted.10,12,13 A healthy child readily tolerates a hematocrit well below 30%. It is our practice not to transfuse otherwise healthy infants up to about 3 months old until their hematocrits have decreased to 20% to 25% and hematocrits of older children have decreased to 20% if there is little potential for postoperative bleeding. The circulating blood volume must be maintained in every case. Observing the operative field to estimate blood loss and monitoring the vital signs, hematocrit, urine output, and the central venous pressure (CVP) help to assess the adequacy of volume replacement. If a procedure is expected to result in significant blood loss or fluid shifts, the anesthesiologist should strongly consider the use of a urine catheter, a central venous line, and invasive arterial monitoring. The child’s size or age should not be a deterrent to the use of a central venous catheter (Table 10-3).


TABLE 10-3 Estimated Predicted Blood Loss and Recommended Monitoring and Equipment
























Predicted Blood Loss Recommended Monitors or Equipment
Less than 0.5 blood volume Routine monitoring
0.5-1.0 blood volume Routing monitoring + urine catheter
1.0 blood volume or more Routine monitoring + urine catheter + CVP + arterial line
1.0 blood volume or more with potential for rapid blood loss Routine monitoring + urine catheter + CVP + arterial line + large-bore IV line + rapid-infusion device
Severe head injury Routine monitoring + urine catheter + CVP + arterial line + large-bore IV line
Major trauma with unknown severity Routine monitoring + urine catheter + CVP + arterial line + large-bore IV line (preferably in upper extremity or central) + rapid-infusion device

CVP, Central venous pressure; IV, intravenous.


There are three approaches for estimating the MABL: an approximation of circulating RBC mass, a modified logarithmic equation, and a simple proportion.14,15 All three approaches yield clinically similar estimates of the MABL. The most straightforward method is to estimate the MABL by simple proportion.14 For purposes of discussion, we use a hematocrit of 25% as the minimum acceptable hematocrit.



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For example, a 10-kg child has an estimated blood volume of 10 (kg) × 70 (mL/kg), or 700 mL. If the child’s hematocrit is 42, the MABL is calculated as follows:



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These calculations only estimate the MABL. The actual hematocrit varies with the child’s preexisting medical conditions, the rapidity of the blood loss, and the rate of concurrent crystalloid replacement.


Initial therapy is directed at replacing fluid deficits and providing maintenance requirements (see Chapter 8). Additional fluid administration is directed at replacing blood loss and third space fluid losses. Although former recommendations for crystalloid replacement of blood loss were 2 to 3 mL per milliliter of shed blood, later studies suggest a smaller volume of replacement, and 1 to 2 mL of isotonic crystalloid or 1 mL of 5% albumin may be adequate.1618 The latter type of replacement is expensive, and there is no clear evidence that colloid is superior to crystalloid.19 New starch volume expanders have been introduced that may hold promise in the future for use in children.


In a 10-kg child with a 700-mL blood volume and 285-mL MABL, the blood loss can be corrected in one of two ways: 570 mL of isotonic crystalloid or 285 mL of 5% albumin. If blood loss exceeds the MABL, or if the hematocrit decreases to 20% to 25% (particularly if additional blood loss is expected during surgery or in the recovery period), transfusion with packed red blood cells (PRBCs) or whole blood (if available) should be started. If postoperative bleeding is likely to occur (e.g., posterior spinal fusion, open heart operations, burn wound excision and grafting), it is reasonable to transfuse to a level greater than the minimum acceptable hematocrit. This is especially true if a greater hematocrit can be provided without the exposure to additional units of blood by completing only the units that are infusing. If 1 unit of blood has been started, it is reasonable to give the child an additional 5% to 10% rather than a fraction of a second unit postoperatively. It is our practice to administer as much of the unit as can be safely tolerated rather than expose the child to another unit of blood postoperatively. Blood banks often prepare several aliquots from one unit, especially for infants, and they can assign one donor unit to a particular child. One part may be given immediately, whereas the second part may be given later; this reduces the risk of exposure to more than one donor for the child.


There seems to be little danger in replacing the MABL entirely with crystalloid provided that the child is healthy and that postoperative oozing will not exceed the MABL. If correction of lost RBCs is necessary, it is simple to calculate the volume of PRBCs needed to return the hemoglobin to an acceptable value. For example, if a 10-kg child’s hematocrit had decreased to 23%, intraoperative or postoperative blood loss is anticipated to continue, and the anesthesiologist elected to increase the hematocrit to 35%, the following calculations can be made:



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Because this volume is less than 1 unit, it may be reasonable to transfuse the child up to a hematocrit of 40% (200 mL PRBCs) to allow an additional margin of safety for postoperative blood loss.



Blood Components and Alternatives


In countries with well-developed health care systems, most whole blood collected from donors is fractionated into components. A unit of whole blood can provide 1 unit of PRBCs, 1 unit of whole blood–derived platelets, and 1 unit of FFP. Apheresis technology can be used to collect any one of these three components selectively. Separation of the individual components from blood allows each to be stored under conditions that best preserve its function: at refrigerator temperature (4° to 10° C) for PRBC, at less than −18° C for FFP, and at room temperature (20° to 24° C) for platelets. Most children with specific disease states (e.g., anemia, clotting factor deficiencies, thrombocytopenia) require only one of these fractions, which is why use of component therapy is widespread. Many blood banks also separate individual units of blood components into smaller-volume pediatric units, so that multiple RBC transfusions can be administered to an infant from a single adult unit.



Red Blood Cell–Containing Components


Blood components containing RBCs are indicated for the treatment of symptomatic deficits of oxygen-carrying capacity.20,21 PRBCs are the most widely available RBC-containing blood component, although in settings where the collection facilities do not have the capability of making components, whole blood may be the only component available. Donor whole blood is collected in a preservative-anticoagulant solution that contains citrate, phosphate, dextrose (glucose), and adenine (CPDA) or just citrate, phosphate, and dextrose. In the latter case, the platelet-rich plasma is removed after centrifugation of the whole blood unit, and a solution containing adenine, dextrose, and occasionally mannitol is added to the PRBCs. The additive-solution systems permit storage for 42 days (compared with 35 days for CPDA) and better preservation of 2,3-diphosphoglycerate (DPG) levels. The characteristics of the CPDA and additive-solution PRBCs and of whole blood are shown in Table 10-4. Although the hematocrit is reduced in the additive-solution PRBCs, the red cell mass is the same.



RBCs carry glycoconjugate antigens of the ABH histo-blood group system on the cell surface that are determined by six common alleles on chromosome 9.19a During the first year of life, infants begin to elaborate alloantibodies to whichever A or B antigens they lack. These isoagglutinins are invariably present after a few months and constitute a formidable immunologic obstacle to transfusion or transplantation across this ABO barrier. The RBCs for transfusion must be compatible with the ABO isoagglutinins of the intended transfusion recipient. Similarly, components with a large volume of plasma (e.g., whole blood, FFP, apheresis platelets) must be compatible with the A or B surface antigens expressed on the recipient’s RBCs. PRBCs must be ABO compatible with the recipient, whereas whole blood must be ABO identical. Table 10-5 summarizes the permissible combinations.



Only RBCs express the Rh(D) antigen. Rh(D)-positive patients may receive Rh(D)-positive or Rh(D)-negative RBCs. Rh(D)-negative patients are routinely given Rh(D)-negative RBCs for any elective transfusions, but in the setting of massive transfusion it may be necessary to switch to Rh(D)-positive RBCs to preserve the supply of Rh(D)-negative RBCs. The blood bank usually determines when to make this substitution based on the inventory and does so more quickly for a patient who is a male or a postmenopausal female (Table 10-6). The objective is to avoid exposing a female with childbearing potential to Rh(D)-positive RBCs and possibly triggering the production of the anti-D alloantibody, which is responsible for the most severe forms of hemolytic disease of the newborn. Table 10-7 shows the common initial volume of PRBCs needed to increase the hemoglobin level by 2 to 3 g/dL.



TABLE 10-7 Common Initial Doses of Blood Components and Expected Effects in Children























Component Dose Effect
Packed red blood cells 10-15 mL/kg Increase hemoglobin by 2-3 g/dL
Platelets* 5-10 mL/kg Increase platelet count by 50,000-100,000/mm3
Fresh frozen plasma 10-15 mL/kg Factor levels increase by 15%-20%
Cryoprecipitate 1-2 units/kg Increase fibrinogen by 60-100 mg/dL

*This recommendation may be reduced pending the impact of the prophylactic platelet dose (PLADO) trial, as published for all age groups40 and for the pediatric age range.40a


The changes that occur to RBC during storage under conventional blood bank conditions has been well described.22 These observations have generated physiologically plausible hypotheses about how such changes may impair the function of the banked RBCs in vivo. The loss of intra-erythrocytic levels of 2,3-DPG and its corresponding decrease in the P50 value may reduce the ability of stored RBCs to relinquish bound O2 compared with 2,3-DPG–replete RBCs. The depletion of nitric oxide (NO) may reduce the vasodilatory properties of the RBCs, hence impairing their ability to maintain the patency of the small vessels in the microcirculation and blood flow to the tissues.23 Numerous changes in the composition and behavior of the RBC plasma membrane, including the loss and oxidation of membrane lipids and proteins and the rearrangement of some membrane constituents,24 correlate with changes in the shape and elasticity of the RBC membrane.25,26 The loss of elasticity in particular can impede the rapid movement of the RBCs through the microcirculation.


These hypotheses and some supportive data from animal models27 have led to a number of clinical studies (mostly in trauma, critical care, colorectal surgery, and cardiac surgery) of outcomes after using stored RBCs, but the results have been inconclusive.2830 About half of the studies found a statistical association between at an unfavorable clinical outcome measure and the transfusion of RBCs, which had been stored for a longer time. However, no association was seen in one half of the studies, including two that were extensions of previous studies with positive findings. A small number of randomized, controlled trials addressed this issue without statistically significant differences in outcomes between patients receiving RBCs stored for different amounts of time,31 although two of them were underpowered.32,33 Knowing that RBCs change during storage raises the question of whether these changes affect the patients in a clinically meaningful way, a question that remains unanswered. Currently, there are four randomized, clinical trials being conducted in North America in populations of especially vulnerable patients: neonates in the intensive care unit, adults in the intensive care unit, and adults undergoing cardiac surgery.3437 The results of these trials should help to guide future transfusion practice.



Platelets


Platelets may be obtained from a whole blood donation or collected by apheresis. Whole blood–derived platelets are separated by centrifugation and suspended in 40 to 60 mL of plasma at a concentration that is two to four times greater than in the circulation. Each unit contains a minimum of 5.5 × 1010 platelets and is stored at 20° to 24° C with gentle continuous agitation for a maximum of 5 days. One unit of whole blood–derived platelets can be expected to increase the platelet count of a 70-kg adult by 5000 to 10,000/mm3 and increase the count in an 18-kg child by 15,000/mm3.38,39 A unit of platelets obtained by apheresis contains at least 3 × 1011 platelets in 200 to 400 mL of plasma, or the equivalent of approximately 6 units of whole blood–derived platelets. A common dose for pediatric patients is 0.1 to 0.3 unit/kg of body weight, or 10 to 15 mL/kg (see Table 10-7); this dose usually produces an increment of 30,000 to 90,000/mm3. However, a rigorous reassessment of platelet dosing was just carried out in the prophylactic platelet dose trial.40,41 Doses equivalent to the standard dose of one pheresis pack (or 6 units) per m2, half of this dose, and double this dose were compared in 1272 adult and pediatric patients who received at least one platelet transfusion. Blood losses were determined with the World Health Organization (WHO) bleeding scale: grade 0 = no bleeding, grade 1 = petechiae, grade 2 = mild blood loss, grade 3 = gross blood loss, and grade 4 = debilitating blood loss. No differences were observed in bleeding outcomes (WHO grade 2 or greater) among the three doses; this was also true for the subset of 200 pediatric patients. The recommended platelet dose may be reduced in the near future, but this change awaits further discussion by the blood transfusion and hemostasis community.4244 This trial did not involve patients undergoing surgical procedures with ongoing blood loss.


In the setting of dilutional thrombocytopenia with ongoing losses or a consumptive coagulopathy (e.g., disseminated intravascular coagulation), larger doses (≥0.3 unit/kg) may be required to boost the platelet count above 50,000/mm3. Because platelets are suspended in plasma that contains the anti-A and anti-B isoagglutinins, they should be ABO compatible with the recipient’s RBCs. Some blood donors have high-titer isoagglutinins that can produce hemolysis in transfusion recipients if a large enough volume of plasma is given.45 The transfusion of plasma-incompatible, whole blood–derived platelets to adult recipients does not produce clinically significant hemolysis because the volume of plasma given is so small relative to the plasma volume of an adult. However, apheresis platelets (and whole blood–derived platelets for small children) should be ABO compatible with the recipient’s RBCs. Because platelets do not express Rh antigens, matching for Rh(D) antigen is not necessary for apheresis platelets because they contain virtually no RBCs. However, whole blood–derived platelets may contain enough RBCs to provoke Rh alloimmunization so platelets from Rh(D)-negative donors are given preferentially to Rh(D)-negative recipients with childbearing potential. If a premenopausal female receives whole blood–derived platelets from an Rh(D)-positive donor, Rh immune globulin can be administered within 72 hours to prevent alloimmunization. Platelets should never be withheld in an emergency situation because of Rh(D) incompatibility.


Platelets are essential to hemostasis associated with the vascular injury of surgery and are necessary for the control of surgical bleeding. Platelets are also required for the maintenance of an intact endothelial barrier to spontaneous blood loss. The number of platelets required to provide adequate hemostasis in the surgical setting is much greater than the level needed to provide prophylaxis against spontaneous hemorrhage. A platelet count of 10,000/mm3 is considered adequate to prevent spontaneous bleeding or bleeding from minor invasive procedures (e.g., lumbar puncture, line placement) in an otherwise stable child. If overt signs of bleeding are present or a more significant hemostatic challenge in the form of a surgical procedure is imminent, a level of 30,000 to 50,000/mm3 may be required.4650 A target level of 50,000/mm3 is appropriate in the setting of massive transfusion.47,5153 Platelets may also be required for children with adequate counts but in whom platelet function is impaired. Many medications (e.g., aspirin; nonsteroidal antiinflammatory agents; dipyridamole; platelet P2Y12 receptor blockers such as clopidogrel or prasugrel; or glycoprotein IIa/IIIb receptor inhibitors such as abciximab, eptifibatide, or tirofiban; serotonin uptake antagonists such as Zoloft) and some conditions (e.g., renal failure with blood urea nitrogen levels above 60 mg/dL) cause abnormal platelet function, which may interfere with surgical hemostasis, in which case it may be necessary to maintain the platelet count at a somewhat greater level, at least until the effect of the medication dissipates or the child’s platelets have largely been replaced by banked platelets.54,55 In a few settings, such as intracranial, ophthalmic, and otologic surgery, even greater levels (100,000/mm3) are sought.


There is no clear-cut threshold below which the platelet count predicts clinical bleeding in the perioperative period. Each child must be individually assessed by constantly observing the surgical field for evidence of abnormal bleeding.56 Unfortunately, we lack a well-validated bedside tool to assess platelet function. The utility of the thromboelastogram and other devices to measure platelet function under controlled flow conditions, such as the platelet function analyzer (PFA-100), are being investigated.5759 The standard technique for diagnosis and evaluation of thrombocytopathies remains Born-O’Brien platelet aggregometry, but it is not useful in the intraoperative setting.60 Most commonly, thrombocytopenia rather than a newly acquired platelet function defect is the problem in the operative setting and massive transfusion.


A child occasionally presents for surgery with a previously characterized platelet dysfunction that may be associated with bleeding. If the child has a normal platelet count, it is reasonable practice to ensure that the blood bank has an adequate platelet supply available for the operating room but to withhold transfusion until the child demonstrates pathologic bleeding.


Several additional points should be considered61:




Special Processing of Cellular Blood Components


Leukocytes collected with whole blood donations partition into platelet and PRBC components, and few intact leukocytes are present in FFP. Passenger leukocytes are responsible for most febrile, nonhemolytic transfusion reactions, HLA alloimmunization, and transmission of cytomegalovirus (CMV). To prevent the complications from these leukocytes, they can be very effectively removed (2 to 3 log reduction) by passage through leukocyte-reduction filters that may be done shortly after collection (prestorage leukoreduction) or at the bedside. Leukocyte reduction of RBCs by filtration is a superior technique to washing or freezing-deglycerolizing, which was used in the past. Table 10-8 provides indications for who may benefit from receiving leukocyte-reduced cellular components (i.e., RBCs or platelets).


TABLE 10-8 Indications for Leukocyte-Reduced Cellular Blood Components



CMV transmission can also be reduced by screening donors for CMV exposure (testing for antibody to CMV), although leukocyte reduction is the more widely used approach. Even though primary CMV infection is benign in children with intact immune systems, some pediatric populations are at risk for developing systemic disease and should be protected from CMV transmission by blood. Only patients who have not previously been infected with CMV (i.e., CMV seronegative) are at risk. Children particularly susceptible to systemic CMV infections are listed in E-Table 10-1.


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E-TABLE 10-1 Children at Risk for Cytomegalovirus Disease*



AIDS, Acquired immunodeficiency syndrome; CMV, cytomegalovirus; HIV, human immunodeficiency virus.


*Applies to CMV-seronegative patients only.


Transfused lymphocytes may mediate a graft-versus-host process in some recipients with impaired cellular immunity. Because this process involves the bone marrow and the usual targets (i.e., skin and gastrointestinal tract), the fatality rate is substantial. Transfusion-associated graft-versus-host disease (GVHD) can be prevented by exposing cellular blood components to gamma irradiation that disables the donor lymphocytes. Children who are considered to be at risk for transfusion-associated GVHD and who should receive irradiated cellular components are listed in E-Table 10-2. This complication can also occur in children with intact immune systems in the unusual circumstance when the transfusion donor is homozygous for an HLA haplotype that is shared with the recipient. In this case, the recipient’s immune system, although fully functional, cannot recognize the donor lymphocytes as foreign. The donor lymphocytes mount a GVHD attack on the recipient’s tissues, recognizing the mismatched haplotype. This situation is more likely to occur when the donor is a blood relative of the recipient. It is for this reason that blood and HLA-matched platelets donated by family members are routinely irradiated.


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E-TABLE 10-2 Children at Risk for Transfusion-Associated Graft-versus-Host Disease



HLA, Human leukocyte antigen system.



Fresh Frozen Plasma


Fresh frozen plasma (FFP) represents the fluid portion of whole blood that is separated and frozen within 8 hours of collection. After thawing at 37° C, which usually requires 30 minutes, it may be administered within 24 hours if stored at 1° to 6° C. The volume of 1 unit varies from 180 to 300 mL and represents 7% to 10% of the coagulation factor activity in a 70-kg patient. It contains all of the clotting factors and regulatory proteins at approximately the native concentration, but after 6 hours at 1° to 6° C, the levels of the labile factors V and VIII begin to diminish.62 FFP does not provide functional platelets, nor does it contain leukocytes or RBCs.


FFP should be ABO-compatible with recipient red cells because it contains the anti-A and anti-B isoagglutinins. If the recipient’s blood type is not known, plasma from a donor with blood type AB, which contains neither anti-A nor anti-B, may be administered. Because the citrate anticoagulant is present in the plasma, rapid administration of FFP is more likely to be associated with citrate toxicity than the transfusion of components with smaller volumes of plasma (e.g., PRBCs).


FFP is frequently administered without justification by evidence-based medicine.63 One major surgical indication for FFP is to correct the coagulopathy associated with massive blood transfusion (see Table 10-7). Other indications include a prolongation in the prothrombin time (PT) before surgery or in the setting of bleeding, the emergency reversal of warfarin, or the presence of a specific congenital or acquired coagulation protein deficiency for which a factor concentrate or a recombinant factor is not available (e.g., for factor XI deficiency).64 Administration of vitamin K should not be overlooked in children who are taking warfarin, have hepatic insufficiency, have been exclusively breastfed,6567 who have been on broad-spectrum antibiotics (which often eliminate normal vitamin K–producing gastrointestinal flora), who have been on total parenteral nutrition for inadequate oral caloric intake, or who may have prolonged hospitalizations. Correction of a mild increase in the PT (e.g., international normalized ratio [INR] <1.5) is rarely necessary. Figure 10-1 shows the relationship between the level of coagulation factors and the in vitro clotting times, in this case the PT. Relatively modest levels of coagulation factors can support normal hemostasis, even though the PT is prolonged. When the PT is very prolonged (see Fig. 10-1, point A), the transfusion of 1 unit of FFP, which increases the coagulation factor levels by 7% to 10% in an adult, has a dramatic effect on shortening the PT. When the PT is only mildly prolonged, as at point C, where factor levels are already adequate for hemostasis, the increase in the factor levels by an additional 7% to 10% with 1 unit of FFP (in an adult) has a much smaller effect on the PT. This small effect does not achieve any improvement in hemostasis.





Plasma-Derived and Recombinant Factor Concentrates


The most commonly administered factor concentrate is factor VIII, used in the treatment of hemophilia A. Children with hemophilia can have many problems related to their disease, including splenomegaly, abnormal liver function, and joint disease related to hemarthrosis. In the past, the use of pooled plasma products was associated with very high rates of transmission of viral hepatitis (especially hepatitis C virus) and HIV.7880 The use of more rigorous viral removal and inactivation processes and the introduction of recombinant factor VIII and IX products8185 have greatly reduced these problems.687586 Initial concerns that there may be an increased incidence of inhibitors in children who receive recombinant therapy compared with plasma-derived factor therapy have not been borne out.87 Mild hemophilia usually responds well to desmopressin (1-deamino-8-d-arginine vasopressin [DDAVP]) therapy.88,89


Children with hemophilia B (i.e., Christmas disease or factor IX deficiency) are managed with recombinant human factor IX and highly purified factor IX (preparations with various amounts of factors VII, X, and prothrombin) that are treated to inactivate or remove viruses.70,71,73,90103 Careful planning of any surgical procedure for these children includes close communication with the child’s hematologist to ensure optimal therapy while reducing unnecessary transfusions (see Chapter 9).


von Willebrand disease is routinely treated with DDAVP or plasma-derived factor VIII concentrates that are also rich in vWF, such as Humate-P, Alphanate, and Koate DVI. In children who have von Willebrand disease and are resistant to DDAVP or for whom DDAVP is contraindicated (e.g., central nervous system [CNS] bleeding, allergic reaction), it is reasonable to withhold treatment with blood-derived products until surgery has begun unless surgery is performed in an area where bleeding is potentially life-threatening, to reduce unnecessary transfusions. These children often do not demonstrate pathologic bleeding. Adjunctive therapies that can further minimize the use of blood products include use of the antifibrinolytic agent ε-aminocaproic acid (Amicar), which can be administered orally or intravenously, and topical hemostatic agents, including topical collagen and fibrin glues.



Desmopressin


DDAVP, a synthetic analogue of vasopressin, can increase the levels of factor VIII : C (i.e., coagulant activity) and factor VIII : vWF in children with mild hemophilia A or von Willebrand disease.89,104108 An IV dose of 0.3 µg/kg (maximum 20 µg; a subcutaneous preparation is available in Europe) increases the levels of both factors twofold to threefold within 30 to 60 minutes, with a half-life of 3 to 6 hours.105 Intranasal DDAVP is also effective, but onset is less rapid. Between 80% and 90% of children with von Willebrand disease are responders,109,110 and affected children should be tested for their responsiveness to IV DDAVP. This treatment is best suited to bleeding from surgical procedures, which ceases within 2 to 3 days. When bleeding continues beyond this period, as can occur with some orthopedic procedures, daily IV Humate P (or Alphanate or Koate DVI) can obviate possible tachyphylaxis with DDAVP. Products rich in the vWF allow better control over peak levels of factor VIII. When in excess of 200%, factor VIII predisposes to postoperative deep venous thrombosis and pulmonary embolism.


DDAVP has been used to treat the coagulopathy associated with uremia and cirrhosis.111,112 It may reduce elective surgical bleeding when the potential for blood loss is substantial, such as in cardiac surgery and spinal fusion.89,113118 Although initial reports apparently demonstrated a benefit in patients who did not have a preexisting coagulopathy, other controlled studies failed to show an effect despite increases in factor VIII:C and vWF, and its use for these indications has largely been abandoned.119121 Because of the potential for hyponatremia from water retention, use of DDAVP is avoided in children younger than 2 years, in children with CNS lesions, including a brain tumor, history of CNS irradiation, or recent neurosurgery or CNS trauma, and in elderly adults.



Albumin, Dextrans, Starches, and Gelatins


Solutions of several high-molecular-weight molecules (i.e., colloids) have been used for volume replacement, although there is no clear advantage to their use over crystalloid solutions. These colloids include albumin, dextrans, starches, and gelatins.


Albumin has the longest track record and the fewest adverse side effects.122,123 In the past, dextrans (i.e., high- and low-molecular-weight glucose polymers) were administered for volume expansion and hemodilution in children,124,125 but currently, their primary use is for antithrombosis, although their value for even this indication is questionable.126


Starches are branched polysaccharide polymers available in high-, medium-, and low-molecular-weight ranges (480,000 to 70,000 daltons). However, these compounds alter hemostasis by diluting clotting factors and impairing platelet function and the coagulation cascade.127,128 An additional concern, especially in children, is their accumulation in the reticuloendothelial system and the potential for unknown long-term adverse effects.129 Several studies have been carried out in children with minor changes in coagulation parameters that occurred when transfusions exceed 20 mL/kg.130134 A 6% hydroxyethyl starch (HES 130/0.4) yielded clinical and physiologic profiles similar to those for 5% albumin in volumes up to 16 mL/kg in noncardiac surgery and in volumes up to 50 mL/kg in cardiac surgery, although at smaller cost.135,136 Several major reviews regarding the use of starches and gels in adult patients who are critically ill have raised significant concerns regarding adverse effects on coagulation137,138 and renal function,139,140 and they found inadequate overall safety data, even for the third-generation products.18,141 If these concerns have been raised in adult populations, we should have even greater concern about their use in children.

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May 25, 2016 | Posted by in ANESTHESIA | Comments Off on Strategies for Blood Product Management and Reducing Transfusions
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