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comprehensive PBM program must include age- and weightappropriate clinical protocols and policies for the management of preoperative anemia, perioperative bleeding, and massive transfusion; these principles are expanded upon in Fig.24.1. Goal-directed transfusion guidelines using restrictive transfusion strategies as supported by evidence are also fundamental components [1, 37, 38].

Preoperative Blood Management andConservation

Patients at risk for intraoperative, allogeneic blood transfusions must be evaluated for preoperative anemia and bleeding abnormalities as indicated by history and examination. Preoperative anemia is widespread, as it is found in about

Fig. 24.1 Illustration of a

comprehensive pediatric patient blood management program with general principles for perioperative blood conservation strategies. PBM patient blood management, ICU intensive care unit, POC point of care

40% of children worldwide and 15–20% of children in industrialized countries [39, 40]. The main etiology is iron deciency, which has a fairly simple treatment plan: iron supplementation [41]. Iron supplementation has been demonstrated to increase hemoglobin levels and decrease blood transfusions, and there is evidence that intravenous iron may result in improved responses as compared to oral iron supplementation [5]. Preoperative anemia, however, is an independent risk factor and is associated with worsened postoperative outcomes in pediatric surgical patients [5, 41–

43]. Although not routinely used, recombinant erythropoie-

tin for stimulation of erythropoiesis has been used successfully in neonates and infants for increasing the hemoglobin concentration prior to surgery. However, recombinant erythropoietin is associated with an increased burden of treatment, as it involves regular subcutaneous injections with

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frequent monitoring of response and iron levels. Nevertheless, it is an additional resource for patients whose parents refuse blood transfusions, whom other causes of anemia have been excluded, or who are poor responders to iron supplementation [5, 27, 41]. In the neonate, important blood conservation strategies also include the delay in umbilical cord clamping and use of umbilical cord blood for initial laboratory sampling upon delivery [38, 44].

Additional blood conservation measures include the

following:

• Standardized guidelines for phlebotomy procedure.

• Obtain blood samples only when necessary.

• Optimize logistics of laboratory blood sampling, for example, bundling of tests.

• Use the smallest collection tube and the minimum acceptable volumes allowable for laboratory testing.

• Remove sampling lines early.

• Return, rather than discard, excess sample volumes to the patient.

• Use point-of-care testing devices.

• Use laboratory equipment needing only small volumes for analysis.

• Use transcutaneous instruments for hemoglobin assessment.

is needed to ascertain the best transfusion strategies for patients with life-threatening bleeding, hemodynamic instability, and cardiopulmonary disease [25]. In select cases (mostly in cardiac surgery when the parents refuse blood transfusions), acute normovolemic hemodilution (ANH) at the beginning of surgery, with return of the autologous blood towards the end of surgery, has been associated with reduction in allogeneic blood transfusions [45]. Currently, there is insufcient evidence to recommend its routine use, although if implemented, institutional protocols should be in place to ensure patient safety [4]. The rst consensus for recommendations for ANH standards and best practices in cardiac surgery, sponsored by the Society for the Advancement of Blood Management and published in 2020, do not address ANH in the pediatric population [46]. A recent statement by the Transfusion and Anemia Expertise Initiative (TAXI) made recommendations for restrictive transfusion practices for the pediatric critically ill patient in the intensive care setting. However, in neonates and premature infants, the evidence supporting restrictive transfusion strategies is unclear [4,

25]. Cell salvage and reinfusion are also techniques shown to

effectively reduce allogeneic blood transfusions; evidence suggests that bowel and cancer surgery are not absolute contraindications for its use. The use of factor concentrates and recombinant coagulation products should be considered as indicated for certain patients [5].

Intraoperative Blood Management andConservation

If possible, surgery should be scheduled for at least 3 weeks after the initial patient evaluation to allow sufcient time for the medical evaluation and treatment of anemia [5]. Intraoperatively, the conduct of the anesthetic and surgery should favor the minimization of bleeding, promotion of hemostasis, and basic non-transfusion techniques for optimization of cardiac output and tissue perfusion (e.g., rhythm, heart rate, preload, contractility, afterload, acid/base status, electrolytes, and temperature). Appropriate surgical techniques and meticulous use of hemostatic topical agents are signicant factors in decreasing surgical bleeding. Recommended multimodal blood-sparing approaches include the avoidance of non-purposeful hemodilution; optimization of acid/base status; focused blood pressure management to avoid hypotension with the judicious use of inotropic support if necessary; avoidance of hypertension to decrease the rate of bleeding; and the concurrent use of antibrinolytics. If signicant bleeding ensues, standardized bleeding management protocols and transfusion algorithms must be in place to guide management. Restrictive transfusion thresholds and goal-directed therapy guided by clinical status and by point-of-care viscoelastic testing are the current standards for most pediatric patients, but further research

Postoperative Blood Management andConservation

Postoperatively, PBM should continue with blood-sparing methods for optimization of tissue perfusion, minimization of bleeding and iatrogenic blood losses, treatment of coagulopathy, and utilization of antibrinolytics as appropriate. Adding vitamin K can help if coagulopathy is present but does not require immediate treatment. If the anemia is not tolerated by the patient, the use of transfusion algorithms with restrictive strategy is recommended as guided by point of–care viscoelastic testing [1, 43, 76].

Blood Management Recommendations forSpecic Surgeries

The aforementioned recommendations are expanded upon in the next section with a focus on specic surgery types. See Tables 24.5, 24.6, and 24.7 for recommendations from major international guidelines, which specically address pediatric PBM for cardiac and other major non-cardiac surgeries as well as special patient conditions. The level of evidence is provided for each recommendation. Published guidelines for pediatric PBM are based on systematic reviews of the pediat-

[

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249

Table 24.5 Patient blood management recommendations for pediatric cardiac surgery

Pediatric cardiac surgery Challenges

Unique cardiac physiology with often reduced reserve margins, e.g., cyanotic disease and parallel circulations Cardiopulmonary bypass (CPB) with associated hemostatic and physiologic derangements Cardiac lesions with varying surgical repair techniques, CPB approaches, and perioperative management methods

Interventions Recommendations Grade

27] BCSH [19] NBA [4] ESA

NATA [

Preoperative

Anemia Treat iron deciency anemia with

Intraoperative

Antibrinolytics Administer lysine analogs 1B 1B R CPB circuit Use miniaturized CPB for neonates

Ultraltration Conventional ultraltration or

Cell salvage Use of cell salvage 1C 1B PP 1B POC testing for

heparin response

AT deciency FFP (10mL/kg) or antithrombin

Protamine dose Protamine dose should be calculated

Hemostasis

monitoring

Postoperative

Restrictive Hb

threshold

CPB cardiopulmonary bypass, R recommendation, PP practice point, PO per os, IV intravenous, ACT activated clotting time, AT antithrombin, POC point-of-care testing, FFP fresh frozen plasma, Hb hemoglobin, PRBC red blood cell

oral or IV iron

Erythropoietin in specic cases 2C

and infants

modied ultraltration for neonates and infants

Whole blood ACT or heparin concentration

supplementation in the presence of heparin resistance secondary to antithrombin deciency

based on heparin concentration Use direct thrombin inhibitors when heparin is contraindicated Monitoring of hemostasis to guide the administration of blood products Blood used for cardiac surgery in neonates and infants should be used before the end of storage day 5

Hemoglobin threshold for transfusion in stable, acyanotic heart disease

Hemoglobin threshold stable, cyanotic heart disease

1C 1B–

1B Evidence is insufcient to make

1B – Hb 7g/dL asymptomatic 1B – Hb 8g/dL with clinical signs suggesting symptomatic anemia 1C– with clinical signs suggestive of symptomatic anemia, Hb 9g/dL

a specic recommendation 1C

2B – Hb 7g/dL asymptomatic 2C – In neonates or actively bleeding or unstable children following CPB, a higher Hb threshold may be appropriate 2C– there is insufcient evidence to make a recommendation for children with cyanotic heart disease

PP-viscoelastic testing

ric PBM literature, which are mostly observational with a paucity of high-grade evidence. Most recommendations were created from evidence where available and expert- based consensus when the evidence is weak or insufcient. Across sets of guidelines, most recommendations are generally concordant with variations from group to group due to different

methodology and reviewers. Procedures usually associated with major blood loss or blood transfusions are cardiac, craniofacial, scoliosis and other major orthopedic surgeries, liver transplantation, and major trauma. Main PBM recommendations rest on preoperative screening for anemia with diagnosis and proper treatment prior to elective surgery, the administra-

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Table 24.6 Patient blood management recommendations for pediatric major non-cardiac surgeries

Major non-cardiac surgeries

Interventions Grade

SABM [

1] NBA [4] ESA [5] BSCH [19]

Preoperative

Anemia: treat

iron deciency anemia with iron

Intraoperative

Hb transfusion

threshold

Antibrinolytic–

administer lysine analogs

Cell salvage 1B

Postoperative

Hb transfusion

threshold

CPB cardiopulmonary bypass, R recommendation, PP practice point, PO per os, IV intravenous, POC point-of-care testing, FFP fresh frozen, plasma, Hb hemoglobin, PRBC red blood cell

The use of antibrinolytics and intraoperative cell salvage collection and re-administration should be considered for all pediatric patients undergoing high blood loss surgery including, but not limited to, cardiac surgery with CPB, craniofacial surgery, and scoliosis/orthopedic surgery

R 1B– PO iron 1C–

R In pediatric patients, including those who are critically ill, a restrictive transfusion strategy is suggested in hemodynamically stable pediatric patients (excluding neonates): Hb concentration<7g/dL, PRBC transfusion is often appropriate. Hb concentration of 7–9g/dL, PRBC transfusion may be appropriate, based on the need to relieve clinical signs and symptoms of anemia. Hb concentration>9g/dL, PRBC transfusion is often unnecessary and may be inappropriate R Antibrinolytics may be considered in large blood loss cases such as scoliosis and craniofacial surgery PP Tranexamic acid should be given within 3hours of traumatic injury

PP In stable pediatric patients (excluding neonates) Hb <7g/ dL, PRBC transfusion is often appropriate PP Hb >9g/dL, PRBC transfusion is often unnecessary and may be inappropriate In preterm infants requiring transfusion, there is insufcient evidence to support or refute the use of either a restrictive or liberal PRBC transfusion strategy

IV iron

We recommend the use of red cell salvage, which is helpful for blood conservation in major cardiac and orthopedic surgery

1C Except for premature babies and cyanotic newborns, hemoglobin targets in bleeding children are 7–9g dL We recommend a target hemoglobin concentration of 7–9g/dL during active bleeding

1C With the exception of children with sickle cell disease, there is no evidence to suggest that children undergoing elective non-cardiac surgery require a higher Hb transfusion threshold than those in PICU (7g/dl, stable patients without major comorbidity or bleeding. Excludes cyanotic children)

2C Tranexamic acid should be given if major blood loss associated with traumatic injury is anticipated 1B Tranexamic acid should be given when there is high risk of signicant bleeding during surgery 2C Red cell salvage should be considered in all children at risk of signicant bleeding undergoing surgery and where transfusion may be required, providing appropriately trained staff are available

1C Hb transfusion threshold of 7g/dL in stable patients without major comorbidity or bleeding

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Table 24.7 Patient blood-management recommendations for pediatric

patients with special situations

Special patients and situations

Grade

TAXI [25] The patient with sickle cell disease

“In children with sickle cell disease who are critically

ill or those at risk of critical illness, we recommend

RBC transfusion to achieve a target hemoglobin

concentration of 10g/dL (rather than a hemoglobin S

[HbS] of <30%) prior to a surgical procedure requiring

general anesthesia”

tion of antibrinolytics, the use of cell salvage, and restrictive transfusion strategies as guided by viscoelastic testing. Recommendations are mostly stratied by the GRADE scale with the exception of the Australian National Blood Authority which uses R (recommendation) if sufciently high quality of data and PP (practice point) if the quality of data is weak [4]. Note that these guidelines often exclude the preterm and neonatal patient populations unless specied, as the evidence is largely inconclusive in these populations.

Blood Management Guidelines: Pediatric Considerations

A signicant number of hospitalized children receive at least one blood transfusion. In fact, more than one-half of extremely low birth weight preterm infants undergo a transfusion during their initial hospitalization [19]. Therefore, the administration of blood products to children requires special consideration. Children and particularly infants have a unique physiology that requires weight-based product dosing, heightened vigilance during large volume transfusions, and special blood banking processes related to a developing immune system. Evidence supporting transfusion thresholds in children stem from a limited number of studies but, in general, evolving standards follow trends adopted in adult blood management. Our understanding of the infant’s coagulation system or potential advantages of clotting factor administration is particularly lacking. Much research needs to be done to more clearly dene rational and evidence-based administration in children, particularly with respect to the long-term effects of restrictive transfusion thresholds.

Adverse Reactions inChildren

Recent reports suggest that children may suffer more adverse transfusion reactions (ATRs) than adults [37, 47, 48]. In particular, febrile nonhemolytic transfusion reactions (FNHTRs) have been reported to occur at a rate ve times that seen in

48]. Because of their relatively small blood volume,

adults [ children are at particular risk of deleterious effects of rapid transfusions. Cardiac arrest secondary to hyperkalemia, particularly in infants, is now established as a known hazard of rapid blood infusion rates [49, 50]. The average potassium concentration of a stored packed PRBC unit is 30–80 mEq/L, which may lead to hyperkalemic cardiac arrest when relatively high blood volumes are administered at a rapid rate [15, 18, 19]. It is recommended that transfusions in small patients be initiated at volumes less than 15–20 mL/kg at of less than 1 mL/kg/min under close monitoring, with a gradual increase in rate as tolerated [13, 19, 51]. Washed packed red blood cells (PRBCs), which have a reduced potassium content, or younger PRBCs (e.g., less than 7 days post-storage) may be requested for small patients requiring large volume transfusions, although existing evidence suggests that if administered at a moderate rate, neonatal outcomes following older versus fresh PRBCs are not signicantly different [

18]. Other ATRs associated with rapid transfusion in chil-

dren, particularly small infants, include ionized hypocalcemia, hypothermia, and volume overload.

Stored blood products contain citrate preservative (citratephosphate- dextrose-adenine; CPDA) as an anticoagulant, which may bind the recipient’s plasma calcium and hinder contraction and relaxation phases of the neonatal cardiac sarcoplasmic reticulum, leading to clinical hypotension [14]. Although this “citrate toxicity” can be seen in patients of all ages, the immature neonatal liver is unable to rapidly metabolize citrate contained in large volume or rapid transfusions. Whole blood, plasma, and irradiated PRBCs contain the highest concentrations of citrate anticoagulant [52, 53]. Because of their relatively large blood volume to weight ratio, children are particularly susceptible to the deleterious effects of transfusion-related hypothermia. A hypothermic child may exhibit decreased drug metabolism, apnea, and a coagulopathic state. When rapid infusion is necessary, PRBC and plasma transfusions should be run through a warming device [13, 15, 51]. Volume overload is also a risk that may not be readily appreciated in the small patient [47]. Transfusion- associated circulatory overload (TACO) is a well-dened ATR that is also seen but not readily recognized during anesthesia and surgery in the adult patient population [54]. There are no specic criteria for TACO in the pediatric population, but a typical presentation intraoperatively may include hypotension, hypoxemia, and bradycardia, nonspecic signs difcult to distinguish from transfusion-related hypocalcemia or hypothermia [47]. A dilutional coagulopathy, either from crystalloid administration or the administration of fractionated blood products absent coagulation factors or platelets, may develop after loss of 1.5–2 blood volumes [15]. A neonate’s ability to regenerate coagulation factors is limited due to hepatic immaturity. Under normal conditions,

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however, tests of hemostasis in the preterm newborn are longer, and in the term newborn, may be are shorter than adult values; the clinical signicance of this is unknown [51].

Pediatric Considerations forPretransfusion Testing andBlood Processing

Children, particularly infants, may require special considerations with respect to pretransfusion testing and blood processing. For example, infants in the rst several months of life have a reduced ability to produce alloantibodies against the major blood group antigens (e.g., A, B, AB, and D) due to an immature immunologic system; alloantibodies in a neonate’s serum are of maternal origin. Therefore, prior to transfusing a young infant, the infant’s pretransfusion testing should be accompanied by a test for maternal blood type and antibodies [13]. As a matter of caution, many transfusion services admin- ister type O, Rhesus(D)-negative (Rh-neg) PRBCs to all infants under 3–6months of age until both infant and maternal blood screening is performed [15]. When performed as a matter of routine, this safety policy may strain a hospital’s O-negative blood supply. Rh-neg cellular blood products (e.g., PRBCs and platelets) and CMV- antibody negative products in general may be distributed in emergency situations for infants and young children for whom pretransfusion testing is unavailable. One concern is that the administration of Rh(D)positive cellular blood products to a Rh-neg infant, or any female of potential childbearing age, may lead to alloantigen sensitization. Rh-neg sensitization may set the stage for Rh-incompatibility that may complicate a subsequent pregnancy or transfusion. Furthermore, Rh-neg sensitization may also lead to extravascular (i.e., delayed) hemolysis that, although typically mild, may lead to signicant morbidity in younger or very small patients. CMV is transported through white blood cells and can have a devastating outcome in susceptible and immunocompromised patients.

Many blood centers only administer blood that is CMVantibody negative to preterm and young infants. Leukoreduction (LCR), under standardized procedure and quality control, removes a substantial quantity of white blood cells from donor products. The majority, but not all, of US blood centers perform pretransfusion leukoreduction of donated cellular blood products. LCR is associated with a substantial reduction in ATRs, including FNHTRs and graft-versus-host disease (GVHD). Administration of blood that is both leukocytereduced and CMV-antibody negative has been shown to effectively eliminate the risk of transfusion- related CMV infection in very low birth weight preterm infants. There is some evidence that leukocyte reduction of blood products prevents or signicantly reduces the risk of CMV in stem cell transplant patients and therefore arguably eliminates the need for CMVnegative blood products in susceptible populations [18].

Blood Preservatives

In an effort to reduce donor exposure, blood banks often release small aliquots of blood from a single donor unit held in preservative. The two main preservatives are AS (adenineglucose- mannitol) and CPDA, and both contain additives that serve as nutrients to the stored PRBCs [13]. Adenine, mannitol, citrate, and dextrose in high concentrations have been associated with renal toxicity (adenine, mannitol), intraventricular hemorrhage (mannitol), hypocalcemia (citrate), and hyperglycemia (dextrose) [13, 55]. Thus, blood stored for neonatal use is often preferentially reconstituted with AS because it extends the shelf life of a PRBC from 35in CPDA to 42days, supporting continued use of a single donor unit [13]. As with the precautionary measures that may be used to prevent hyperkalemia, small volume (e.g., <20mL/kg), slow-rate infusions have not been shown to be a preservative-related problem in preterm infants [13, 18, 55].

Packed Red Blood Cell (PRBC) Transfusion Guidelines

A decision to transfuse must be based on a consideration of the patient’s full clinical prole, including cardiorespiratory disease, pending interventions, rate of blood loss, and comorbidities that may impact systemic oxygen delivery, rather than a single laboratory value at one point in time [3]. Furthermore, anemia should always be addressed and managed prior to making a decision to administer blood [43]. As in the adult patient population, a restrictive PRBC transfusion threshold may reduce the number of PRBC units transfused in stable, hospitalized children without an increase in untoward outcomes [30–34]. The World Health Organization (WHO) and several African societies set a transfusion threshold at 5g/dL for symptomatic children, suggesting that this degree of anemia in asymptomatic children may be a new cutoff for transfusion avoidance in resource-poor environments [56]. A recent consensus group of international experts, the TAXI Initiative, also recommended a transfusion threshold of 5g/dL in critically ill children without certain comorbidities when considering the hemoglobin value alone [25]. In 2019, a consensus statement was developed to guide PRBC transfusions in children undergoing cardiac surgery [27]. Further studies in both cyanotic and acyanotic children undergoing cardiac surgery have lent support to the shortterm safety of lower PRBC transfusion thresholds in the pediatric cardiac patient population [57, 58].

Transfusion thresholds for preterm infants, a unique patient population with rapidly changing physiological needs, are currently based on gestational age and cardiorespiratory status [19]. Neonates are typically transfused at a higher hemoglobin value than older infants and children

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[14]. Several randomized controlled trials have examined restrictive versus liberal transfusion thresholds in very low birth weight premature infants, with conicting short-term outcome results [59–61, 67]. Systematic reviews conclude that despite a decrease in donor exposure and lower hemoglobin values, treatment endpoints and long-term outcomes remain unclear in the restrictive strategy [32, 33]. A recent multicenter trial (the ETTNO Randomized Clinical Trial) examined long-term outcomes in infants at 2years corrected age who had birth weights less than 1kg and concluded that the rate of disability and death were unaffected using a restrictive red blood cell transfusion threshold versus a more liberal one [62]. The thresholds for transfusion were based on individual patient factors such as postnatal age and illness acuity. A pending multicenter study, The Transfusion in Prematures (TOP) Trial will further examine longer term outcomes associated with a liberal versus a restrictive red blood cell transfusion threshold in extremely low birth weight infants. Tables 24.8 and 24.9 contain suggested

Table 24.8 PRBC transfusion guidelines for prematurea and young

infants (<4months PNA)

Postnatal ageb (PNA; days) Hemoglobin (g/dL)

Requiring

support 0–7 11.5 10 8–14 10 8.5 > 14 8.5 7.5 Acute blood loss, symptomatic Congenital heart disease Cyanotic: 9g/dL if symptomatic anemia

CNS bleeding <7–10g/dL

Symptomatic anemia <8g/dL

Premature indicates an infant less than 37 weeks corrected gestational

age

Postnatal age (PNA) indicates the chronological age, or time elapsed

birth

Respiratory support is dened as a need for mechanical support venti-

lation or FiO

An otherwise stable infant with bradycardia/tachycardia, poor weight

gain, or apnea

> 25%

10% of total blood volume

Acyanotic: 7g/dL; symptomatic anemia:

8g/dL

respiratory

No respiratory support

PRBC transfusion guidelines based on hemoglobin value in infants.

Children tend to be managed according to adult PRBC guidelines and expert opinion [55]. Anemic children with a chronic medical condition may be physiologically compensated and are often transfused at lower hemoglobin values. As Table 24.10 demonstrates, current international PRBC trigger guidelines are similar, with slight variation during the rst weeks of life.

Plasma Transfusion Guidelines

Plasma may be the most overly administered blood product available and is often administered based on laboratory values alone [19, 63]. In general, coagulation factor levels in infants tend to be lower than those of older children and adults, but the clinical signicance of this difference is unknown [19, 64] (Table24.11). Despite differences in coag- ulation factor levels, conventional test results of coagulation are often treated similarly between infants and older children [51]. As a result, routine coagulation screening may lead to inappropriate transfusions, particularly in the neonate where there is heightened anxiety over bleeding potential including intraventricular hemorrhage (IVH) [51, 65, 66]. In the absence of confounding variables that may increase bleeding risk, only 10–40% of coagulation factor activity levels are needed to achieve hemostasis. Furthermore, there is no evi-

Table 24.9 PRBC transfusion guidelines for older infants (≥4months

PNA)

Symptomatic anemia: Hgb<7g/dL Perioperative anemia with anticipated blood loss: Hgb<8g/dL Congenital heart disease Cyanotic: 9g/dL if

Acute blood loss with hemodynamic instability Acute traumatic brain injury <10g/dL

Chronic transfusion regimen (e.g., sickle cell anemia, thalassemia, leukemias) Hgb<7g/dL

symptomatic anemia Acyanotic: 7g/dL; Symptomatic anemia: 8g/dL 8g/dL

Table 24.10 RBC transfusion practices

Overview of international guidelines for red blood cell transfusions

British Committee for Standards in Haematology 2016 [19]

Postnatal week

Week 1 10–12g/dL <10g/dL 11–13g/dL 10–12g/dL <11.5g/dL <10g/dL <11.5g/dL <10g/dL Week 2 9.5–10g/dL <7.5g/dL 10–12.5g/dL 8.5–11g/dL <10g/dL <8.5g/dL <10g/dL <8.5g/dL Week ≥3

Modied from Ree and Lopriore [75]

For example, supplemental oxygen, high-ow nasal cannula, CPAP (continuous positive airway pressure), positive-pressure ventilation

Respiratory

support

8.5–10g/dL <7.5g/dL 8.5–11g/dL 7–10g/dL <8.5g/dL <7.5g/dL <8.5g/dL <7.5g/dL

No respiratory support

Australian National Blood Authority 2016 [4]

Respiratory support

No respiratory support

Canadian Blood Services 2017 [64]

Respiratory support

No respiratory support

Dutch Guidelines Quality Council (Concept) 2018 [74]

Respiratory support

No respiratory support

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Table 24.11 Screening laboratory tests for hemostasis: neonates ver-

sus adults

aPTT Longer Longer 16years Prothrombin time Thrombin time Bleeding time Longer PFA-100 Longer

ROTERM/TEG

Clotting time Same Shorter 3months Clot formation time Maximal clot rmness

Modied from AABB Technical Manual, 19th ed, originally from Revel-Vilk aModied with permission from Revel-Vilk bMaximum age reported cIn samples drawn in the rst 7 to 10days of life aPTT activated partial thromboplastin time, PFA platelet function analyzer, ROTEM rotating tromboelastometry, TEG thromboelastography

Preterm neonates vs. full-term neonates

Longer Same or

Same Shorter 3months

Stronger Stronger 3months

Neonates vs. older children/ adults

longer

longer Shorter 1month Shorter 1month

Approximate age adult values are

reached

16years

5years

dence that an international normalized ratio (INR) value between 1.6 and 2.0 is indicative of future bleeding risk in either the adult or pediatric patient populations [13, 51]. When available, the specic coagulation product should be utilized to replace inherited or acquired coagulation deciency, rather than plasma. Recombinant coagulation products available include factors VIII, IX, VIIa, XI, and XIII, prothrombin complex concentrate (factors II, VII, IX, X), antithrombin III, protein C, and C1 esterase inhibitor. Absolute contraindications to plasma transfusion in all age groups include volume expansion and nutritional replacement therapy. A suggested plasma transfusion volume is 10–20mL/kg at an initial rate of 1mL/kg/min that is gradually increased as the patient is evaluated for signs of citrate toxicity (e.g., hypocalcemia and hypotension). This dose of plasma may result in an increase in coagulation factor levels by approximately 15%, with a clinical effect lasting less than 12hours [13]. Recommended indications for plasma therapy in children and neonates include the following.

Neonates

1. Treatment of clinically signicant bleeding in the face of abnormal coagulation parameters

2. Prior to an invasive procedure in the face of abnormal coagulation parameters

3. Treatment of severe hereditary protein S deciency

4. Treatment of protein C deciency if recombinant factor is unavailable

Children

1. Coagulation factor consumption including disseminated intravascular coagulation (DIC)

2. Prolonged PT/aPTT >2 times midpoint normal range for age prior to an invasive procedure

3. Urgent warfarin reversal when prothrombin complex concentrate is unavailable or contraindicated (e.g., HIT (heparin- induced thrombocytopenia))

4. Treatment of idiopathic thrombotic thrombocytopenic purpura (ITP)

5. Treatment of bleeding for acquired or inherited factor deciencies when specic factor concentrates are unavailable

6. Plasma exchange

Platelet Transfusion Guidelines

Sepsis, maternal disorders such as preeclampsia, the presence of intravenous catheters, and low blood levels of endogenous erythropoietin contribute to a high incidence (20–70%) of thrombocytopenia in preterm neonates, resulting in a high rate of platelet transfusions [18]. Platelet transfusions in children are associated with more ATRs than other fractionated blood products [47]. The threshold for a platelet transfusion usually hinges on whether the goal is to prevent future bleeding (e.g., prophylaxis) or to stop active bleeding in the face of thrombocytopenia. The denition of thrombocytopenia has been dened as 150 × 109/L in both children and adults [13]. From the neonatal period through adulthood, platelet counts are similar. Neonatal platelets may be larger and exhibit greater adhesion and faster clot initiation, although the clinical signicance of this nding is unknown [19]. Taken as an isolated nding, a platelet count alone does not always predict a patient’s risk of bleeding. Patients with a platelet count as low as 50×109/L may have normal coagulation in the absence of confounding variables such as cardiopulmonary bypass circuitry, drug administration, or an alloimmune process.

In general, platelet transfusion trigger guidelines for

infants and older children tend to reect adult guidelines [68]. A platelet count of 100×109/L was once the standard for surgical hemostasis; however, with ongoing clinical experience (including the high rate of ATRs associated with platelets), the suggested transfusion threshold for major non-neuraxial surgery has decreased to 50×109/L.Recent adult studies support a count of 20 × 10 venous catheter placement [68, 69]. Although controversial, the minimum acceptable count for diagnostic lumbar puncture, a procedure frequently performed in children with a defect in platelet production, has been 10×109/L for many years. Following a systematic review and expert consensus,

/L for central

24 Pediatric Blood Management

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255

this newly recommended threshold is 50× 109/L, despite supporting evidence that is of very low quality [69]. In a recent retrospective study of 900 propensity-matched, critically ill adult patients, there was no benet following prophylactic platelet transfusions in nonbleeding patients with platelet counts as low as 20× 109/L, putting into question all current guidelines [70]. Presumably because of a per-

(HUS), either because of a risk of continued consumption (such as in ITP), or an increased risk of thrombosis [13, 64]. For children undergoing cardiopulmonary bypass or extracorporeal life support (ECLS), platelet transfusions are recommended in the face of excessive bleeding unresponsive to other measures such as heparin reversal, although a threshold

of 100×109/L has traditionally been chosen [27]. ceived risk of IVH, sick preterm infants and neonates often receive platelets at a higher threshold (e.g., 20–50×109/L), when a stable, nonbleeding infant or older child is unlikely

Cryoprecipitate Transfusion Guidelines

to have signicant bleeding at platelet counts as low as 10 × 109/L [13]. A recent multicenter trial (PLANET-2) examined 660 premature infants and found less 28-day mortality or episodes of major bleeding when applying a prophylactic transfusion threshold of 25 rather than 50×109/L [71].

Platelet transfusion triggers suggested in a variety of clinical situations are listed in Table 24.12. Ideally, platelets should be ABO-compatible with the recipient’s blood type, because if not ABO-identical, the response as measured by platelet count may be decreased [13]. Furthermore, because all platelet preparations contain a small number of PRBCs (possibly 0.5 ml/unit), ideal donor platelets are Rh(D)identical to prevent anti-D alloimmunization. A dose of ~5–10 mL/kg should increase a patient’s platelet count by ~50–100×10

/L.In the absence of life-threatening bleeding, platelet transfusions should not be given in the face of idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), heparin-induced thrombocytopenia (HIT), or hemolytic uremic syndrome

Cryoprecipitate is a precipitant of fresh frozen plasma. The pediatric literature lacks clinical trials comparing differing cryoprecipitate dosing regimens or indications. There is no evidence supporting the benet of prophylactic use of cryoprecipitate, including prior to invasive surgery. Typically administered to replace brinogen, a single cryoprecipitate unit contains factor VIII (80mg), brinogen (150mg), factor XIII (up to 30% that is contained in original plasma), and von Willebrand factor (up to 70% that is contained in original plasma) in a total volume of 10–15ml [13]. It does not have to be ABO-compatible when used for non-neonates, and its small volume comparatively reduces the risk of uid overload often seen when plasma is used to treat clotting factor deciencies. ABO-compatibility is recommended for use in neonates secondary to their small size and concerns over hemolysis due to the alloantibodies that may be contained in the precipitate [13]. Specic virus-inactivated factor concentrates such as recombinant factor VIII, von Willebrand factor complex, or brinogen concentrate should be administered in lieu of cryoprecipitate when these products are available.

Table 24.12 Platelet transfusion triggers

Platelet transfusion triggers by count (109/L)

Prophylactic transfusion

Prematurity (<37weeks PCA) <25 Term infants (>37weeks PCA) <4months old <20 >4months old <10 Prior to lumbar puncture <50 Patient scheduled for major invasive procedure Qualitative platelet defect (congenital or acquired) CNS procedure <100 Central venous catheter placement Tunneled: <50

Fetal and neonatal alloimmune thrombocytopenia (FNAIT)

Patient has an FNAIT-affected sibling <20–30

Bleeding patients

Active bleeding <50 Intracranial bleeding <100 Diffuse microvascular bleeding, ECLS, cardiopulmonary bypass Qualitative platelet defect Any platelet count if

<50

Any platelet count if bleeding

Non-tunneled: <20

Stable patient: <20–30 Unstable patient: <50

<100

bleeding

A “pooled” unit of cryoprecipitate is the product of 5–6 donors (~100–130ml) and, although heat-treated, may theoretically present an infectious and alloimmunization risk. Recombinant brinogen concentrate is not yet FDAapproved in the United States for the treatment of acquired hypobrinogenemia.

10–15ml] per 10kg body weight, which can be expected to increase the child’s brinogen level by 50–100mg/dL [13]. A generally accepted threshold for cryoprecipitate transfusion in the setting of clinically signicant bleeding is 100mg/ dL.Other indications include the following:

1. Disease states with evidence of brinogen consumption

2. Hypobrinogenemia and a pending invasive procedure.

3. Bleeding following cardiac or other major surgery with

4. Inherited defects of brinogen, either quantitative (e.g.,

The recommended dose for cryoprecipitate is 1 unit [e.g.,

including DIC with bleeding.

evidence of low brinogen level.

abrinogenemia, congenital hypobrinogenemia, Kasabach- Merritt syndrome, or hemangioma with thrombocytopenia) or qualitative (e.g., brinogen Cleveland, brinogen Marburg, etc.).

256

M. M. Sheth et al.

https://t.me/medicina_free

5. As treatment for hemophilia A or vWF disease in the

absence of a response to desmopressin or availability of specic recombinant factor concentrates.

6. Platelet dysfunction in the face of uremia and hemodialy-

sis is not available.

7. Fibrin sealant.

Conclusion

In conclusion, pediatric PBM consists of a customized blood conservation strategy, individualized to each patient according to their age and clinical condition. Fundamental considerations include attention to anemia, maintenance of hemoglobin concentration, optimization of hemostasis, and minimization of blood loss. Although the medical literature does not contain an abundance of evidence supporting blanket application of pediatric PBM principles, transfusion trigger thresholds have decreased as supported by an increasing number of trials. An interdisciplinary approach to patient blood management along with a dedication to education, quality control, and monitoring of institutional behavior is essential to sustained PBM practices. Education with a focus on the unique physiology of blood loss and replacement in children is imperative for patient safety. Most importantly, pediatric PBM is conrmation that we always act in the best interest of our patients.

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