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Pediatric blood loss can be a major concern during neurosurgical procedures, particularly during craniosynostosis, scoliosis, and tumor surgeries. When surgery is performed on young patients, such as craniosynostosis surgery, it is further complicated by lower preoperative hemoglobin levels and larger amounts of blood lost relative to total blood volume. This is due to hemoglobin levels reaching their physiological nadir (9–12 g/dL) at around 8 to 12 weeks of age.1 The infant head receives a proportionately greater percentage of blood volume,² and this also contributes to a greater relative blood volume loss during cranial surgery. Moreover, fetal hemoglobin has a higher affinity for oxygen, such that less oxygen is off-loaded to tissues, which may accentuate the effects of blood loss in newborns and infants.³

Blood loss can lead to major complications. According to the Pediatric Perioperative Cardiac Arrest (POCA) registry, 12% of intraoperative cardiac arrests in children are secondary to hypovolemia resulting from blood loss, with the majority of these events occurring during neurosurgical procedures.⁴ This clearly demonstrates that the pediatric neurosurgeon needs to consider blood loss very carefully, and plan strategies to minimize the risks posed to the child.

When compared with adults, children have higher rates of transfusion-related adverse events.⁵ In children, the most common adverse event seen in data collected through the Serious Hazards of Transfusion (SHOT) scheme in the United Kingdom was transfusion of an incorrect blood component, accounting for 82.2% of all adverse events.⁶ Other adverse events reported included acute transfusion reactions, delayed transfusion reactions, transfusion-related acute lung injury (TRALI), transfusion-associated graft-versus-host disease, and transfusion-transmitted infections.⁶ Infants seem to be at particularly high risk and have rates of adverse reactions nearly triple that of adults. Although adults have an estimated incidence of transfusion-related adverse events of 13 per 100,000 red cells, the incidence of an adverse event is estimated to be 18 per 100,000 red cells issued for children under 18 years old, and this number climbs to 37 per 100,000 for infants under 12 months of age.⁶ Despite the fact that these overall complication rates are low, many physicians and certainly the general public remain concerned about transfusions, particularly in children.⁷ Strategies to minimize blood loss and minimize the need for allogeneic blood transfusions are therefore of paramount importance in pediatric neurosurgery. This importance is reflected in the wealth of research and literature dedicated to treating and preventing pediatric blood loss during neurosurgical procedures. This chapter examines hematologic adjuvant treatments currently in use, and summarizes the recent evidence.

Venous thromboembolic events (deep venous thrombosis or pulmonary embolism) can be considered rare in this pediatric neurosurgery patient population and are not reviewed in this chapter.

Preoperative Strategies

There is much that can be done preoperatively to reduce the need for an allogeneic blood transfusion during surgery. The optimization of hematocrit (Hct) preoperatively is important, as a low Hct is predictive of an increased requirement for allogeneic blood transfusion.8 Furthermore, higher preoperative Hct levels facilitate a preoperative autologous donation (PAD), a strategy that can reduce the risk of receiving an allogeneic blood transfusion, which is discussed below.

Iron Supplementation

Preoperative iron supplementation has been shown to decrease the proportion of patients requiring blood transfusions in adults.⁹ It can be administered either orally or intravenously. Although there is insufficient evidence to support its routine preoperative use, it is inexpensive and has been used successfully as an adjunct to erythropoietin therapy to increase Hct in pediatric patients undergoing surgery where major blood loss is anticipated.^10,11

Erythropoietin

Studies looking at erythropoietin therapy to increase preoperative Hct have shown promise. In a randomized controlled study by Krajewski et al,¹² the use of preoperative erythropoietin or Procrit (a recombinant protein that augments erythropoietin populations), given as weekly subcutaneous injections starting 3 weeks before surgery, increased preoperative Hct by 56.2% in children undergoing craniosynostosis surgery. Furthermore, the use of this strategy, in conjunction with intraoperative blood salvage, resulted in significantly lower allogeneic transfusion rates (5% vs 100% of the control group), as well as lower mean volumes transfused per patient (0.05 pediatric units versus 1.74 pediatric units in the control group). Similar studies have been done in pediatric spine surgery.¹³ Erythropoietin is particularly useful in patients who are unable or unwilling to receive blood transfusions.

Preoperative Autologous Blood Donation

Preoperative autologous blood donation (PABD) is a strategy whereby patients donate autologous blood that can be transfused as needed intraoperatively, thus reducing the need for allogeneic blood. It is a reasonable option for pediatric procedures where the amount of blood loss is expected to be at least 20% of the total blood volume.¹⁴ In pediatric neurosurgery, PAD is mainly used in scoliosis surgery, as patients tend to be older and are better able to tolerate donation. PAD is generally restricted to children who weigh over 20 kg but has been used in children as young as 3 months and with weights as low as 5.8 kg.^15,16 It has the advantage of reducing the exposure of children to multiple donors and alleviates the demand on blood bank resources. Intraoperatively, it has the advantage over cell salvage of being ready to use without having to wait for a sufficient amount of blood loss/collection. In a review of 17 studies of PAD in children, allogeneic transfusions were avoided in 63% to 95% of patients through the use of PAD.¹⁴ Autologous blood wastage rates varied widely from 15 to 64%.¹⁴ The optimal time to donate continues to be a matter of some debate. Longer intervals between donation and surgery allow for compensatory erythropoiesis to increase red blood cell volume, but carry the risk of hemolysis, which increases with longer storage intervals.

Directed donation is a process that allows family members to donate blood, in preparation for the patient’s surgery, that is reserved specifically for the patient. Although this option may be appealing to parents based on the assumption that this strategy might decrease the risk of infectious complications, a survey done at the Hospital for Sick Children in Toronto found that directed donors had 10-fold higher rates of transmissible disease compared with volunteer donors.17 However, this study did find that directed donation reduced exposure to multiple donors in an estimated 28% of patients, which is an important consideration for children who are at high risk of antibody formation when they receive blood products from several different donors. Some authors have raised the concern that directed donation carries a greater risk of the rare but highly lethal complication of graft-versus-host disease due to fact that human leukocyte antigen (HLA) homozygosity is more likely to occur among first-degree family members.¹⁸ Added to these risks are the ethical considerations of the loss of anonymity between donor and recipient, and the possibility of coercion into donation, as some family members may feel emotionally pressured to donate. In light of this, directed donation is not practiced routinely at most institutions.

Intraoperative Strategies

Intraoperative Blood Salvage

Intraoperative cell salvage systems are a commonly used blood-conservation technique whereby blood lost intraoperatively is collected, filtered, and transfused back to the patient once a sufficient quantity is available. A recent survey of current practice paradigms estimated that it is used in 26% of all craniosynostosis surgeries.¹⁹ Pediatric-sized systems have been developed and consist of downsized collection bowls. In adults, a recent Cochrane meta-analysis on the use of Intraoperative cell salvage showed an absolute risk reduction of receiving an allogeneic blood transfusion of 21%.²⁰ In pediatric neurosurgery, cell salvage has been shown to be effective at reducing exposure to allogeneic blood transfusion in scoliosis and craniosynostosis surgery.^12,21,22 The main concern with intraoperative cell salvage is the risk of biological contamination. Microbiological growth in blood samples recuperated via cell salvage has been reported to be 38.5 to 68.4%.^23,24 Despite these seemingly high contamination rates, no postoperative cultures were positive for the same species of bacteria found in the recuperated samples, suggesting that the reported contamination may not be clinically relevant.

Hypervolemic Hemodilution

Hypervolemic hemodilution (HH) involves hemodiluting a patient through infusion of a colloid solution, usually hydroxyethyl starch. Because this technique involves dilution of the patient’s circulating blood volume, the blood lost intraoperatively will have a lower hematocrit, and a smaller red blood cell mass will be lost. Moreover, hemodilution improves tissue perfusion as decreased blood viscosity leads to decreased peripheral resistance. There is evidence that it is effective at reducing the amount of allogeneic blood transfused during scoliosis surgery in children.25

Acute Normovolemic Hemodilution

Acute normovolemic hemodilution (ANH) also relies on the principle of hemodilution as a blood conservation strategy. It differs from HH in that an equal volume of blood is removed and stored before crystalloid or colloid infusion to keep the total blood volume stable. Advocates of this technique have argued that it carries the advantage over intraoperative cell salvage of being able to rapidly transfuse blood without having to wait for a specific quantity of blood loss to be recuperated and filtered. Despite these theoretical advantages, there is insufficient evidence to support the routine use of this technique.²⁶ In a pediatric-specific randomized controlled study on patients undergoing craniosynostosis repair, the use of ANH had no effect on the amount of allogeneic blood transfused, risk of exposure to allogeneic blood, or the hematocrit value at hospital discharge.²⁷ Furthermore, HH is simpler to use than ANH, and mathematical models have suggested that HH confers similar benefit and may be safer than ANH, particularly when blood losses are less than 40% of total blood volume.²⁸

Deliberate Hypotension

The deliberate induction of hypotension is a controversial technique where blood pressure is lowered intraoperatively to minimize blood loss. In pediatrics, mean arterial pressures (MAPs) of 50 to 65 mm Hg or a MAP reduction of 20% have been used as targets.²¹ This technique carries the risk of ischemia, and is contraindicated in patients with hypovolemia, elevated intracranial pressure, or decreased end-organ blood flow. Although potentially useful in older children undergoing spine surgery, deliberate hypotension is of limited use in cranial pediatric neurosurgery where cerebral perfusion is of paramount importance and with vasoactive anesthesia agents that induce a baseline level of hypotension to begin with.

Antifibrinolytics

Fibrin is the most basic structural element of a blood clot. Antifibrinolytics reduce perioperative bleeding by inhibiting the degradation of fibrin. The most commonly used antifibrinolytic drugs are aprotinin, tranexamic acid, and aminocaproic acid.

Aprotinin is a nonselective serine protease inhibitor derived from bovine lung. It acts via direct inhibition of plasmin, trypsin, plasma-kallikrein, and tissue-kallikrein.^29,30 Tranexamic acid and ∊-aminocaproic acid are synthetic lysine analogues that competitively inhibit activation of plasminogen to plasmin, a molecule responsible for the degradation of fibrin.

Several clinical trials have shown that antifibrinolytics such as aprotinin, tranexamic acid, and aminocaproic acid are effective at reducing blood loss and transfusion requirements in children undergoing neurosurgery.^31,32 A Cochrane review done in children undergoing scoliosis surgery found that the risk of being transfused was similar in patients receiving antifibrinolytic drugs or placebo, but antifibrinolytic drugs decreased the amount of blood transfused and the amount of blood lost.30 There is evidence that aprotinin may be more effective than other antifibrinolytics at reducing intraoperative blood loss.^33,34 However, it was withdrawn from the worldwide market in 2007 after the Canadian antifibrinolytic trial (Blood conservation using Antifibrinolytics in a Randomized Trial [BART]) found an increased 30-day mortality and risk of cardiovascular complications with aprotinin when compared with other antifibrinolytics.³³

Recombinant Factor VIIa

Recombinant factor VIIa (rFVIIa) is a hemostatic agent that enhances localized thrombin generation on thrombin-activated platelets at the site of injury, thereby enhancing platelet adhesion and aggregation.³⁵ It is currently licensed for use in hemophiliac patients with inhibitors, but is being used off-label in certain unique situations to control intraoperative bleeding or neonatal intracranial hemorrhage in nonhemophiliac patients.^36,37 The evidence to support its use intraoperatively is weak and largely based on subjective assessments of its hemostatic ability. In a recent retrospective review of 388 pediatric patients treated with off-label rFVIIa, 82% had subjective decrease in bleeding after its administration.³⁵ There are only a few case reports and one case series addressing its use in pediatric neurosurgery, but the results are promising.^38–40 In one case series by Heisel et al,³⁸ rFVIIa was administered intravenously to eight pediatric patients to control life-threatening bleeding that failed to respond to standard neurosurgical technique and blood product replacement. In all but one case, there was an excellent response to rFVIIa with control of bleeding and successful completion of the procedure. One concern with the use of rFVIIa is the risk of thromboembolic adverse events. However, in two reviews of pediatric cases in which rFVIIa was used, the incidence was fairly low at 0.8 to 5.4%.^35,41

Desmopressin Acetate (DDAVP)

Desmopressin acetate (deamino-8-D-arginine vasopressin, DDAVP) is a vasopressin analogue that has been used to correct bleeding time and provide surgical hemostasis for patients with von Willebrand disease, acquired platelet disorders, and uremia.⁴² It has also been used in normal patients to reduce blood loss during certain surgical procedures including cardiac surgery and complex spine surgeries. In adult studies, prophylactic DDAVP has been shown to reduce blood loss and transfusion requirements.⁴³ In pediatric neuromuscular scoliosis, a randomized controlled trial showed that the administration of DDAVP immediately following induction of anesthesia resulted in a 19% reduction in overall blood loss, although this difference failed to reach significance.⁴²

Transfusion Protocols

Transfusion triggers vary in different centers and depend on the particular clinical situation. During periods of rapid blood loss, hemodynamic parameters may be used to guide transfusion. For example, low hemoglobin/hematocrit levels in the presence of hypotension, tachycardia, metabolic acidosis, decreased peripheral perfusion, or low urine output may warrant transfusion.

Absolute transfusion triggers have been used by some institutions. A common threshold for transfusion is a hemoglobin level of less than 7 to 8 g/dL or a hematocrit of less than 0.21 to 0.3.12,44 In our institution, we have accepted hemoglobin levels as low as 5 g/dL in hemodynamically stable children as part of our initiative to decrease the rates of blood transfusion. Abandoning strict transfusion thresholds in conjunction with technical adjustments has decreased our transfusion rate from 42% to 11% in patients undergoing sagittal craniosynostosis correction.⁷

There is increasing evidence that the use of transfusion algorithms can reduce allogeneic blood transfusions.^45,46 In a randomized trial of 637 critically ill children, a transfusion threshold of 7 g/dL for red blood cell transfusion decreased transfusion requirements by 44% without an increase in adverse events.⁴⁶ Moreover, 54% of patients in the restrictive-strategy transfusion group received no transfusion compared with only 2% in the liberal-strategy group.

Many clinicians advocate abandoning liberal transfusion strategies, and only providing transfusion at low hemoglobin thresholds (e.g., hemoglobin 7 g/dL), coupled with clinical evidence of hemodynamic instability.

Conclusion

The prevention and treatment of intraoperative blood loss is an important aspect of pediatric neurosurgery, as even a small volume of blood may represent a significant proportion of the child’s total blood volume. Furthermore, children have a higher incidence of transfusion-related adverse events, so reducing exposure to allogeneic blood products should be a key part of their perioperative management. In elective cases, erythropoietin and iron supplementation can be useful to augment Hct preoperatively. Preoperative autologous donation can be considered in select cases. Hemodilution strategies can be effective in reducing the risk of receiving an allogeneic blood transfusion, as they minimize the red blood cell volume lost for a given blood volume. Intraoperative blood salvage is now widely used in pediatric surgery, and there is good evidence that it reduces allogeneic blood transfusion rates. When blood loss is difficult to control intraoperatively, several agents may be used to achieve hemostasis, including antifibrinolytics, recombinant factor VIIa, and desmopressin acetate. Finally, the use of transfusion triggers and protocols has been shown to reduce the frequency of blood transfusions in children and should be implemented whenever possible.