Fibrinogen concentrate (HaemocomplettanP/RiaSTAP; CSL Behring, USA) has been marketed for a number of years for the treatment of congenital hypofibrinogenemia but has been advocated as a fibrinogen replacement therapy for patients requiring massive transfusion (79). It is produced from pooled human plasma by fractionation and undergoes inactivation steps; it has a fibrinogen concentration of approximately 20 mg/mL. Despite the evidence supporting maintenance of adequate fibrinogen levels in bleeding patients, little data are available on the administration of fibrinogen concentrate to trauma patients. In pediatric trauma, the use of a fibrinogen concentrate was recently reported in a 7-year-old patient with severe abdominal and pelvic trauma (80). On arrival to the emergency department, he received 250 mL RBC, 250 mL crystalloid, and 0.5 g fibrinogen concentrate, which were given preemptively. He then underwent goal-directed hemostatic therapy using RoTEM. A total of 2 g fibrinogen was administered, whereas fresh-frozen plasma (FFP) and platelets were avoided. Despite an estimated blood loss of more than 70 mL/kg, the patient received only 3 units of RBC. The ratio of intraoperative fibrinogen concentrate (g) to RBC (U) was 0.7, which is similar to the ratio of 0.9 described by Schochl when looking at thromboelastometry-guided coagulation factor concentrate–based therapy versus FFP in adult trauma (81). Fibrinogen or cryoprecipitate (for fibrinogen replacement) received a grade 1C recommendation in a recent European guideline for management of traumatic bleeding in adult patients with thromboelastometric signs of fibrinogen deficiency or a fibrinogen level of less than 1.5 to 2.0 g/L and significant bleeding (82).
Recombinant factor VIIa was initially developed for the treatment of hemophilia and acquired inhibitors, but off-label use of rFVIIa has become increasingly prevalent. Recombinant factor VIIa has a more developed presence in the pediatric literature than that of the other factor concentrates. Its effectiveness in neonates, infants, and children with TIC and clinically significant bleeding, as well as complications after its administration in pediatric patients, has been described in several reports. A retrospective case series of 135 pediatric patients receiving rFVIIa for off-label use revealed its potential for clinical utility in the setting of surgery and trauma. In this case series, 15 patients received rFVIIa for trauma, 19 patients for surgical bleeding, 16 patients for procedural prophylaxis, and 28 patients for bleeding resulting from disseminated intravascular coagulation/sepsis. There was a decrease in 24-h median transfusion volume after rFVIIa administration. Surgical patients had control of life-threatening bleeding with low associated mortality. Indeed, the mortality rate was significantly lower in the surgical/trauma patients (16%) in comparison with that in medical patients (58%). Major thrombotic events were seen in three patients after rFVIIa, resulting in two deaths and one leg amputation (83). Another case review study on pediatric patients with severe TIC after cerebral injury reports a rapid correction of hemostatic abnormalities after administration of a bolus of 90 μg/kg rFVIIa in three children aged 5 weeks, 20 months, and 11 years (84).
Dosing recommendations in the pediatric patient are extrapolated, in part, from the adult literature, supplemented by the pediatric hemophiliac population. Bolus doses have ranged from 40 to 100 μg/kg in the nonhemophiliac pediatric population. With ongoing bleeding or risk for bleeding, repeat doses at intervals of 2 to 6 h have been administered. In addition to bolus dosing, continuous infusion (20–30 μg/kg per h) after the bolus to maintain hemostatic levels of rFVIIa has been reported. Compared with adults, the pharmacokinetics in pediatric patients demonstrates a shorter half-life and an increased clearance (85). In addition to its effects on coagulation function, recent data report enhanced platelet function (84), suggesting a potential role in patients with qualitative platelet disorders, which may include severely injured pediatric trauma patients, more specifically, brain-injured children. However, some limitations in the use of rFVIIa have been observed in adults. Data from 21 institutions and 380 patients were collected from the Western Trauma Association Web-based registry and revealed several indicators of poor response to rFVIIa, including acidosis (pH <7.2), thrombocytopenia (platelets, <100,000), and hypotension (systolic blood pressure, ≤90 mmHg). Based on these results, maximal benefit cannot be achieved with administration late in the treatment of a hemorrhaging trauma patient (86).
Prothrombin complex concentrate, also referred to as factor IX complex, is derived from pooled human plasma and contains 25 to 30 times the concentration of clotting factors as FFP. Four-factor PCCs contain factors II, VII, IX, and X, whereas 3-factor PCCs contain little or no factor VII. Depending on the formulation, PCCs may additionally contain PC, protein S, AT, and low-dose heparin (87). Most formulations available in the United States are 3-factor PCCs and are approved for prevention and control of bleeding in patients with hemophilia B. However, because of the availability of highly purified and recombinant factor IX products, PCCs are rarely used for this indication. There have been no controlled clinical trials evaluating the use of PCC in massive bleeding; recommendations are generally based on retrospective or observational studies, case reports, and expert opinion (87). Literature regarding use of PCC in the pediatric trauma patient is scarce. One case report described an 8-kg infant with liver trauma and severe hemorrhage who was acidotic (pH 6.67) and severely anemic with a hemoglobin count of 4 mg/dL (88). The patient underwent two surgical procedures and transfusion of packed RBCs, platelets, and FFP. After the second operation, the infant continued to bleed despite the administration of FFP, platelets, and RBCs. Vitamin K and 30 IU/kg PCC were administered because of ongoing hemorrhage, at which point there was rapid cessation of bleeding and the INR decreased from 2.9 to 1.5.
The variability in factor concentration between formulations creates challenges in standardization of dosing. When using the package information regarding dosing recommendations for hemophilia B, an expected increase in factor IX between 20% and 50% would occur with a dose of 20 to 50 units/kg (89). Similarly, Australasian guidelines recommend a dose of 25 to 50 units/kg of 3-factor PCC to reverse INR after administration of vitamin K antagonists (90). Caution must be exercised in administration of these agents because of their activity as potent procoagulants (91). Patanwala recommended a maximum cumulative dosage of less than 50 units/kg because of the risk of thromboembolism (89). Although some studies have shown benefits of PCC, there is currently only level 2C evidence (GRADE working group) for its usage in patients with massive bleeding in concert with FFP (87). In the European guidelines for management of traumatic bleeding, it is only recommended for the emergent reversal of vitamin K–dependent anticoagulation (grade 1B recommendation) (92). For stronger recommendations to be developed for use in hemorrhage secondary to trauma, there is a need for randomized studies to evaluate outcomes after administration, especially in children.
Tranexamic acid, an antifibrinolytic agent, is a synthetic lysine analog that functions by competitive inhibition of the enzymatic activation of plasminogen to plasmin, responsible for the degradation of fibrin. The Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) investigators revealed a significant decrease in death secondary to bleeding when TXA was administered early after trauma. Despite this favorable outcome, several gaps in knowledge regarding the use of TXA in trauma were identified in a recent review by a US Department of Defense Committee. Many issues raised are important in the pediatric population as well, including the need for a more clear-cut identification of which patients might benefit from TXA, the development of animal models to establish efficacy and safety, and further evaluation of the safety profile of TXA given the increased risk for thrombotic events and the lack of data regarding safety in children (93). A 2008 systematic review analyzing the use of TXA in pediatric patients undergoing spine surgery revealed six studies. Tranexamic acid led to a modest decrease in volume of blood transfused, but not the number of patients requiring transfusion. No deaths or major adverse events were reported; however, the number of patients was too small and follow-up duration was too brief to draw conclusions regarding safety (94). Similar results have been found in pediatric cardiac literature (95).
The Royal College of Paediatrics and Child Health and the Neonatal and Paediatric Pharmacists Group Medicines Committee published an evidence statement in November 2012 addressing the use of TXA for major trauma in children in response to CRASH-2. This evidence statement strongly encouraged the need for ongoing research into the use of TXA in the pediatric population but offered pragmatic dosing guidelines based on extrapolation from adult literature because published use of TXA in pediatric patients has revealed wide variability in dosing. The recommendation by this group was a 15-mg/kg loading dose (maximum, 1 g) for 10 min followed by 2 mg/kg per h for at least 8 h or until bleeding stops. Because no indication recommendations were given, the group urged caution with administration of TXA in the pediatric trauma population because a potential risk of thrombosis exists (96). This stance was supported by Reade and colleagues (97) who encouraged the further evaluation of the safety and efficacy of TXA in trauma patients before its universal protocolized use.
In the adult trauma setting, resuscitation strategies have evolved with a trend toward the early and liberal use of blood products, including RBC, FFP, and platelets in patients with hemorrhagic shock. Several studies have supported the use of a 1:1:1 platelet/FPP/RBC ratio when transfusing severely injured patients (13, 14, 98, 99). However, the results of these studies may have been affected by survival bias (100–103). Other published studies have not shown any improvement in survival using this approach (104–106). In contrast, two recent studies have still shown a benefit of using a high FFP-blood ratio after adjusting for survival bias (107, 108). Regardless of these results, a higher ratio transfusion approach has been adopted at the majority of level 1 adult trauma centers, and prospective, randomized, controlled trials are currently underway to determine optimal ratios for patients with severe hemorrhagic blood loss (109).
Massive transfusion in children is uncommon, and in non-neonatal pediatric patients, transfusion guidelines are similar to those in adults. In children, because blood volume varies per age, gender, and weight (110–112), it is unclear as to what constitutes a massive transfusion. Moreover, the response to massive bleeding in children is thought to differ from the adult response because of their greater physiological reserve and an improved tolerance of blood loss (113). Data analyzing the effects of a balanced ratio of blood product component administration in massive transfusion are limited in pediatric populations. To date, only three single-center studies have been reported on experience with MTP in pediatric patients (Table 3). A prospective study on 102 pediatric trauma patients was completed after the institution of a pediatric MTP and outcomes compared with a period before protocol implementation (110). After MTP institution, the median FFP/RBC transfusion ratio was 1:1.8 compared with a ratio of 1:3.6 in the pre-MTP patient population. Although this study was not powered to show improvement in outcome, there were two important findings. First, the majority of patients had at least one coagulation value abnormality. Second, implementation of a pediatric MTP with early and aggressive use of plasma transfusion in children with TIC was feasible. In the same year, Chidester et al. (113) performed a prospective cohort study of 55 children, of whom 22 patients received transfusions according to MTP whereas the other 33 patients received blood at physician discretion. Similar to results reported by Hendrickson et al. (110), mortality was not significantly different between the two groups. However, the MTP group received a greater overall amount of blood products and was more likely to be severely injured. Thromboembolic events were observed exclusively in the non-MTP group, which the authors attributed to undertransfusion in those patients. Importantly, despite using an MTP, neither study was able to reach the protocols’ goal of 1:1 ratio for FFP/RBC transfusion because of the lack of availability of thawed plasma. Recently, a retrospective study on 105 pediatric trauma patients receiving massive transfusion found no association between blood product ratios and survival (114). Interestingly, all casualties suffered from severe TBI (head AIS, ≥3) and not hemorrhage. Taken together, additional prospective randomized clinical trials are needed to fully evaluate the effectiveness of varying ratios of blood component therapies in the pediatric trauma population.
Fresh-frozen plasma is the most common blood component transfused to treat coagulopathy. Fresh-frozen plasma is plasma produced from whole blood and frozen to -40°C to preserve labile coagulation factors. Fresh-frozen plasma typically contains coagulation factors close to normal blood levels as well as other plasma proteins, including immunoglobulins and albumin. Volume is a potential disadvantage of using FFP in the pediatric trauma setting where TIC may be present and rapidly progressing, but no volume expansion is needed. Most guidelines suggest that plasma should be only transfused in the case of active bleeding and not based on abnormal coagulation screens alone (115, 116).
There are inherent risks to the transfusion of FFP. These risks include, but are not limited to, exposure to pathogens, transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload, and adverse immunological reactions. In a retrospective study, Karam et al. (117) found a 3-fold increase in risk of new or progressive multiple organ dysfunction syndrome in pediatric patients receiving one or more plasma transfusions. Those patients receiving plasma also had an increase in nosocomial infections and intensive care unit length of stay. Another retrospective study compared trauma patients receiving FFP alone versus coagulation factor concentrates (fibrinogen and PCC) and no FFP. Although mortality was similar, patients receiving FFP received more packed RBCs and had an increased frequency of multiorgan failure (118). Recently, a solvent/detergent–treated plasma has been licensed in the United States; this product has been shown to dramatically reduce the risk of adverse advents associated with single-donor FFP, including reduced TRALI (119). The application of solvent/detergent plasma needs to be explored to determine if its use is safer but equally efficacious compared with the use of regular FFP in pediatric trauma patients who are both coagulopathic and hypovolemic.
Advantages of coagulation factor concentrates include immediate availability for administration, lack of excessive volume expansion, standardization of factor concentration and dose, and lack of elevated risk of TRALI (120). In addition, coagulation factor concentrates have a minimal risk of pathogen transmission because they undergo viral inactivation steps. However, it should be pointed out that plasma may have protective properties that are unrelated to its procoagulant activity but are related to the restoration of the endothelial glycocalyx layer that is damaged by hypoperfusion and hypoxia (121).
In summary, pediatric data on successful management of TIC are limited, and practices are largely extrapolated from the adult trauma experience. Few studies have directly looked at hemostatic interventions in children. It is clear that TIC accompanying pediatric trauma is an area where future prospective randomized trials are needed to define ideal treatment strategies necessary to improve outcomes in this unique patient population.
Coagulation abnormalities after pediatric trauma are more common than previously thought and are associated with increased morbidity and mortality. Essential prerequisites needed to investigate coagulation abnormalities after trauma in the pediatric population are the accurate interpretation of coagulation tests, along with a thorough understanding of the normal postnatal development of the human coagulation system. The laboratory-assisted diagnostic approach to several hemostatic disturbances in the newborn and the child is challenging because collection procedures and coagulation assays must be adapted for very small amounts of blood, and the reference intervals for many assays may differ broadly from those for adults. Measurements of viscoelastic properties of whole blood provides a rapid evaluation of clot dynamics in whole blood and are of greater value than coagulation screens in diagnosing and managing TIC. A number of interventions have been undertaken in trauma patients to minimize TIC and hemorrhage, including balanced MTPs, factor concentrate administration, and antifibrinolytic therapy. Despite these interventions, hemorrhage remains the second largest cause of death in adult trauma patients and is responsible for one half of the deaths occurring in the first 24 h (122). The widespread application of adult traumatic coagulopathy management principles to pediatric traumatic coagulopathy management should not be done blindly, and caution needs to be applied in the care of these patients. The mechanisms behind the development of ATC in the pediatric population need to be elucidated, and well-designed prospective clinical trials studying the efficacy of early detection and management in TIC after pediatric trauma are urgently needed.
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