Management of neonatal massive hemorrhage: A narrative review

Massive hemorrhage in neonates is life-threatening, requiring prompt recognition and management, and multi-disciplinary teamwork to achieve best outcomes. A multi-center study of neonates admitted to neonatal intensive care (NICU) reported a 25% incidence of any episode of bleeding, 11% of which were categorized as major or severe.1 Neonates have distinct physiological differences which influence transfusion management; however, current evidence guiding management of massive hemorrhage in this high-risk population is limited.2, 3 Current neonatal massive hemorrhage guidelines are adapted from weight-based pediatric and adult recommendations, with wide variation between institutions.2, 3 This review encompasses neonatal physiology relevant to massive hemorrhage, management principles, and the current evidence, to inform evidence-based recommendations. Management of major hemorrhage during cardiac surgery is beyond the scope of this review. Studies using traditional coagulation testing (including prothrombin time, activated partial thromboplastin time, thrombin clotting time, plasminogen, clotting factor, and inhibitor assays) have demonstrated that the differences in coagulation between healthy preterm and term infants are minor.4 The period between 30 and 40 weeks' gestation is not associated with rapid changes in the coagulation system. Postnatal maturation of coagulation factors toward adult levels is accelerated in preterm infants. By 6 months of life, preterm and term infants have equivalent coagulation systems.4 However, these studies are limited by their small sample size and correlation of these laboratory differences with clinical bleeding risk was not investigated.4 Studies using contemporary viscoelastic coagulation tests have shown accelerated initiation of coagulation, increased clot strength and increased fibrinolysis in healthy neonates compared to older children and adults, with preterm neonates exhibiting a more hypocoagulable profile compared to term neonates.5 However, evidence on how this correlates with clinical bleeding risk is lacking and normal reference ranges for viscoelastic coagulation tests in neonates are yet to be established.5 Neonates have underdeveloped circulatory reflexes and their total blood volume is small. Hence their physiological reserve and ability to tolerate major blood loss is limited.6 The fetal myocardium contains less contractile units and mitochondria compared to adult myocardium, resulting in poorer contractility and compliance of the left ventricle, particularly in preterm neonates. This results in impaired diastolic relaxation, reliance on active atrial contraction for ventricular filling and limited preload reserve. Increases in systemic vascular resistance can cause a reduction in cardiac output before a reduction in blood pressure is observed.7-9 In addition, the adaptive responses in other neuro-endocrine systems such as in the autonomic nervous system and hypothalamic–pituitary axis (relative adrenal insufficiency) are limited and likely contribute to cardiovascular instability.10, 11 Compared to the adult myocardium, the neonatal myocardial sarcoplasmic reticulum is less able to store and release calcium. Therefore, neonatal cardiac function depends on calcium delivery to the myocardium. Calcium causes an increase in myocardial contractility, peripheral vasoconstriction, and increased systemic vascular resistance, and may stimulate catecholamine release from the adrenal gland. It is common to see an increase in blood pressure immediately following intravenous calcium administration.12 Neonates are susceptible to hypothermia and thermoregulation is impaired proportionally to the degree of prematurity. Each one-degree difference in core temperature, results in a 10% decrease in coagulation activity with significant impairment of hemostasis at core temperatures ≤34°C.13 Hypothermia is independently associated with neonatal mortality and morbidity and is a predictor of adverse outcomes in massive hemorrhage.14 Blood volume is approximately 90 mL/kg in the term neonate and 100 mL/kg in the preterm neonate, compared to 70–80 mL/kg in older children.15 Due to a lower total blood volume, a small volume of blood loss in the neonatal period represents a proportionally greater overall loss and therefore neonates are more likely to require blood transfusion (for example, during surgery or frequent blood sampling for laboratory monitoring).16 High oxygen affinity fetal hemoglobin comprises around 70%–90% of total hemoglobin at birth. Fetal hemoglobin less readily releases oxygen to end organs, disadvantaging the neonate during massive hemorrhage.15 Preterm delivery results in impairment of adequate postnatal erythropoiesis with a progressive reduction in fetal hemoglobin levels over the first 2 weeks of life.17 Levels of most coagulation factors increase with advancing gestational and postnatal age. The neonatal period is characterized by decreased levels of all coagulation factors, except for factor 8 and von Willebrand factor, which are increased. Anticoagulant factors, including antithrombin and protein C and S, are also decreased and take months to years to reach adult levels. While fibrinogen levels are normal, thromboelastometry studies suggest that it is relatively dysfunctional, existing in a fetal form until 12 months of age.18 Clot structure is altered with a reduction in fibrinolytic activity.19 Despite these differences, the neonatal hemostatic system is still functionally balanced with no tendency toward coagulopathy or thrombosis in the healthy term neonate, as measured by bleeding time using standardized devices.18 Neonates have similar platelet number and volume to adults with platelet levels increasing from 2 to 4 weeks of age.20 However, preterm infants may have a lower platelet count than term infants. 30% of all neonates requiring NICU admission and up to 70% of those defined as extremely low-birth-weight have platelet counts of 100 to 150 × 109, reflecting their reduced marrow reserve.20 Consequently, it has been argued that a different definition of thrombocytopenia should be applied to neonates of different gestational ages.21 In in vitro assays, platelets in neonates demonstrate decreased responsiveness and function compared to adults.21, 22 However, most in vivo assays do not show platelet dysfunction. Indeed, bleeding times and thromboelastometry coagulation times suggest that under physiologic conditions, neonatal platelets are as efficient as adult platelets.18, 21, 22 The definition of massive hemorrhage in neonates is based upon pediatric trauma literature, and is typically defined as the anticipated or actual administration of >40 mL/kg of blood products in a 24-h period.6, 23, 24 In the newborn, the most common etiologies are feto-maternal hemorrhage and antepartum hemorrhage due to placental abruption or vasa previa.6 Other causes include sub-galeal hemorrhage related to instrumental delivery, major surgery such as laparotomy for necrotizing enterocolitis and iatrogenic causes such as an accidentally dislodged arterial line.6 In the setting of feto-maternal hemorrhage, the volume of blood loss required to cause shock in the newborn is variable and dependent on the feto-placental blood volume (approximately 120–130 mL/kg), rapidity of blood loss, gestational age, placental function, fetal growth and concurrent fetal hypoxia.25 Assessment and recognition of shock in the neonate after birth can be difficult particularly with concealed losses.26 Neonates are vulnerable to the development of coagulopathy during massive hemorrhage due to hypothermia, acidosis, and hemodilution.6 Hypothermia may occur rapidly due to blood loss, the large body surface area to weight ratio of neonates, and iatrogenic factors including the administration of cold blood products and low ambient temperatures. Acidosis may develop due to hemorrhagic shock, sepsis, and tissue damage. Hemodilution as a direct consequence of crystalloid, colloid and blood product transfusion may cause a relative deficiency of coagulation factors, fibrinogen, and platelets.6 The substantial citrate content of packed red blood cells (RBC) contributes to hypocalcemia which further exacerbates coagulopathy.6 While neonatal RBC transfusion may improve cerebral oxygenation, resulting in lower risk of death and/or improved neurodevelopmental outcome, concerns remain about transfusion exposure and increased risk for common neonatal morbidities.27 The two largest randomized clinical trials comparing liberal (high) versus restrictive (low) thresholds for RBC transfusion in very preterm neonates, the Transfusion of Prematures (TOP) trial and Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants (ETTNO) trial, show no benefit of transfusion at a higher threshold on both short term and two-year outcomes.28, 29 In both trials, transfusion thresholds were similar and guided by algorithms depending on postnatal age and requirement of respiratory support (Table 1). A subsequent systematic review proposed a consensus statement recommending low transfusion thresholds for RBC transfusion in preterm neonates (<30 weeks gestational age) as shown in Table 2.30 These studies provide guidance for the relatively stable preterm baby; however, the relevance to acute blood loss is limited. In the high-stress situation of neonatal massive hemorrhage, a damage control approach may be more appropriate with one universal hemoglobin threshold for neonates of all chronological ages to act as a guide to clinicians until a more clinically stable situation is achieved. Currently, there is no evidence to recommend a hemoglobin transfusion threshold specific to neonatal massive hemorrhage; however, given that this population often requires additional respiratory support, it would seem reasonable to have a minimum threshold of 90 g/L.28-30 The PlaNeT-2 trial demonstrated that preterm neonates who received a platelet transfusion at a threshold of 50 × 109/L had a significantly higher rate of death or major bleeding within 28 days of randomization than those who received a transfusion at 25 × 109/L.31 However, only neonates without a history of major bleeding in the preceding 72 h were eligible for enrolment, significantly impacting the relevance of this finding to neonates who have massive hemorrhage and evidence of ongoing active bleeding. The optimal platelet transfusion threshold in neonates with massive hemorrhage and active ongoing blood loss remains a significant knowledge gap. There is a paucity of neonatal-specific evidence to guide transfusion thresholds for fibrinogen supplementation, with most guidelines based on adult data or consensus opinion.32, 33 The most recent British Committee for Standards in Hematology guidelines recommend a fibrinogen target of >1.5 g/L in major neonatal hemorrhage, while the Australian National Blood Authority guidelines suggest a target of >2 g/L.2, 32 Traditional coagulation tests, such as activated partial thromboplastin time (APTT) and international normalized ratio (INR), have been the mainstay for evaluation of hemostasis in neonates.33 However, these tests only assess procoagulant factors without assessing anticoagulant, cellular, and fibrinolytic activities. There are no studies which demonstrate the threshold for INR or APTT at which a neonate is at increased risk of clinically significant bleeding. Consequently, the use of these tests alone to inform transfusion decisions is not recommended.34, 35 These tests may have long turn-around times (at least 30 min), limiting their use in critical bleeding situations where immediate blood product administration is required. They require a large sample of blood (0.8–3 mL), contributing toward iatrogenic anemia.33 Viscoelastic coagulation testing (VCT), such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM), is a promising alternative to traditional coagulation tests in neonates. VCT provides a comprehensive assessment of clot kinetics from clot formation to fibrinolysis. It provides rapid, real-time, bedside assessment of coagulation, allowing tailored blood product administration, potentially reducing overall blood product administration.36 In neonates, TEG-guided administration of fresh frozen plasma (FFP) has been associated with reduced intraoperative FFP use during surgery (31% vs. 60%, p < .001).37 Results have shorter turn-around times (5 min) and may require a smaller volume of blood (300 μL to 2.7 mL) compared to traditional coagulation testing.36, 38 Given the small total blood volume of a neonate, the traditional method of transfusion RBC, plasma and platelets in ratios of 1:1:1 carries a risk of volume overload and unnecessary transfusion. Early use of viscoelastic hemostatic assays to guide blood product choice may therefore be helpful in minimizing the risk of volume overload and allow targeted goal-directed therapy in neonates.39 The European Society of Anesthesiology and Intensive Care (ESAIC) 2022 guidelines recommend utilizing viscoelastic hemostatic assay guided interventions to guide transfusion in neonates during non-cardiac and cardiac surgery (Grade 2C evidence). There are many limitations to this recommendation; reference ranges for TEG and ROTEM in neonates are not standardized, are often based on adult data, and may not accurately reflect neonatal hemostasis.40 Several studies have contributed valuable data on neonatal reference ranges and highlight the need for further research to refine these values for different neonatal populations.38, 41-43 While viscoelastic tests have shown potential for guiding transfusion decisions and predicting bleeding risk, there is a need for more clinical trials to validate their role in neonates. VCT may not be available in some institutions, and in a situation with extremely rapid blood loss, it may not be practical. Repeated blood sampling can be a significant iatrogenic loss in low-birth-weight neonates.44 There is minimal evidence to support specific transfusion thresholds in an acutely bleeding neonate; however, the Australian National Blood Authority guidelines recommend the transfusion targets listed in Table 3.2, 20 Transfusion decisions should not be based on laboratory testing alone and should take into consideration the clinical situation, hemodynamic stability, and ongoing bleeding risk. Activation of a massive transfusion protocol is recommended when there is estimated blood loss of >40 mL/kg in 24 h with hemodynamic instability with or without ongoing blood loss.23, 45 However, this requires measurement of the amount of blood that was lost or transfused over a period of time which is impractical in a rapidly evolving, critical bleeding event. Ideally, the massive transfusion protocol should be activated early to optimize patient outcomes. Therefore, we suggest practitioners consider activating the protocol based on clinical suspicion, when there is both active blood loss and hemodynamic instability. Stored blood has a lower 2,3-diphosphoglycerate content, decreased red cell deformability and reduced adenosine triphosphate content, resulting in red cells that do not delivery oxygen to tissues as effectively as fresh red cells.6 Despite this, a large randomized controlled trial demonstrated that the administration of “fresh” RBC cells (≤7 days old) compared to “older” RBC (up to 42 days old) had no effect on the incidence of major neonatal morbidity (including necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, or infection) or mortality.46 Washed red cells reduce the potassium, cytokine, complement protein and red cell microparticle content of the transfused pack, but it is unknown if this has clinical benefit.2, 6, 47 The WashT Trial aims to determine the clinical effect of transfusion with washed versus unwashed red cells in extremely preterm newborns and may answer this question.47 Currently standard treatment for patients experiencing hemorrhagic shock employs balanced transfusion of blood components.48 However, compared to whole blood concurrent transfusion of blood to achieve a balanced transfusion is more The role of low whole blood as an treatment for pediatric trauma patients with hemorrhagic shock is increasing While use is more common in the adult a study reported the use of for pediatric massive transfusion in only of for pediatric While studies have reported the of use for other pediatric requiring massive transfusion beyond evidence for use in neonates is limited. and reported their of as a to acute blood loss in preterm neonates with a gestational age of that it was and use should be While data is studies in other patient with small sample demonstrate a similar rate of adverse when or are with a there is very low of the Therefore, a role for in neonates based on a small given the and potential if available use may be for bleeding. is is that optimal for and outcomes in the preterm newborn population remain unknown with further of role in neonatal massive transfusion required. and fibrinogen may be to fibrinogen in massive hemorrhage with a of evidence to support use of one over the other in this is a cold protein from The of using are low and that it contains additional clotting factors including and include the time required for the lower of fibrinogen volume and the higher risk of adverse such as and transfusion is from plasma and is as a that is by with of this product in neonates is the smaller required to be vs. mL/kg for and more given the may be more prompt as is not it has lower of adverse and is in It is more than and not available in all are from the adult population and recommend mL/kg with until bleeding is of fibrinogen by and it is recommended to the product for It is recommended that fibrinogen with early transfusion independently associated with reduced early mortality at 6 and 24 h in children with reduced fibrinogen is from the of plasma using the Blood It contains fibrinogen, factor and von Willebrand factor, and may be in neonates to fibrinogen deficiency in the of massive It is immediately available as it can be at for up to days after However, there are no clinical trials comparing it with or fibrinogen many as of and infants a transfusion of FFP has been proposed to have in this population and has the that it can be rapidly for FFP contains plasma including coagulation factors, acute and protein C and It also contains coagulation factors and However, while it may be for the management of coagulopathy by coagulation factors, there remains limited direct evidence in This is further by the normal coagulation factor reference ranges in neonates and the optimal transfusion as guided by viscoelastic testing and traditional coagulation tests and prothrombin still FFP is also for volume in an to increase cardiac and end oxygen delivery, with a recent study of in 22 European that of FFP were given for volume and reduced also in an with of the resulting in cell coagulation, and a that FFP may However, potential an evidence-based review of the available clinical data not support use as a volume in the neonatal and it remains unknown if it provides a clinically significant benefit in an bleeding neonates the use of blood and and increased ambient is should be for example, using an clot formation by the on the In the adult and pediatric the use of is independently associated with a decrease in mortality following massive hemorrhage, however, no studies have preterm The 2022 guidelines recommend the use of in neonates non-cardiac surgery that is associated with high-risk However, this is based on a pediatric study with a small number of neonates who cardiac The National Blood Authority that should be in pediatric patients or There is minimal evidence to support an optimal in neonates. Despite this, a of by of 2 until bleeding has been proposed in neonate specific massive transfusion in clinical use in the and 3 massive hypocalcemia may occur due to the citrate content in transfused red It is to and normal calcium levels using calcium administration during massive hemorrhage to optimize myocardial function and blood while also minimizing administration is recommended as rapid administration may be associated with or and may cause tissue A of factor for bleeding only use in adults with a bleeding such as and has not been shown to reduce There is some evidence that factor increase morbidity and mortality in pediatric patients cardiac There is no evidence for use in neonates and is therefore not 40 Massive transfusion can be in neonates but has been associated with higher of compared to older Neonates and infants one of pediatric adverse include acute circulatory overload and these potential remain defined in the neonatal studies have reported between RBC and major neonatal such as bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, hemorrhage, and studies have that platelet transfusion may cause in neonates of of death or major bleeding have been shown with higher platelet FFP may also be associated with adverse including and circulatory Management can be helpful for clinicians to reduce and in There are two consensus for the management of pediatric critical however, do not for management requires multi-disciplinary including transfusion and A Massive Transfusion may between these provide a standardized management and reduce in recognition and There is that remains unknown in the management of massive transfusion in neonates. research include the of normal reference ranges for VCT in neonates and optimal for laboratory and of blood or colloid administration during major hemorrhage and the effect this has on neonatal morbidity and mortality also be studies are required to determine neonates benefit from ratios of blood products versus targeted transfusion based on the potential for as an alternative to with blood requires further given the current limited data in the neonatal This review the current evidence and knowledge in massive transfusion in neonates. Despite the limited evidence clinicians and may massive transfusion for neonates with critical bleeding to between in management, and Early use of viscoelastic hemostatic assays to guide blood product choice may be helpful in minimizing the risk of volume overload and allow targeted goal-directed therapy in neonates, limitations in this patient by and of the by and of the by and and of the by all by as of the the of The have no of not to this as no were or during the current