Six-year-old Rhaenyra is brought into the emergency department after being hit by a car.
On primary survey, she is found to be tachycardic and hypotensive, with bruising over her abdomen.
She may have a life-threatening major haemorrhage.
What is major haemorrhage?
Surprisingly, there are different definitions of paediatric major haemorrhage, with no single agreed-upon definition.
These definitions include blood loss of 40 mL/kg over 24 hours, transfusion of ≥50% of total blood volume in 3 hours, transfusion of 100% of total blood volume in 24 hours, and bleeding with clinical signs of hypovolaemic shock that is unlikely to be controlled. This makes comparing data across research trials challenging.
Many of these definitions are not useful in acutely bleeding children as they require measuring the amount of blood that was lost or transfused over prolonged periods. As such, clinicians often activate the major haemorrhage protocol based on clinical suspicion, mechanism of injury and the clinical signs of shock.
What is the ‘diamond of death’?
Major haemorrhage from trauma can lead to trauma-induced coagulopathy, a process of abnormal bleeding and clotting. This is associated with multiple organ failure and death. Factors which can worsen bleeding and associated complications are described in the ‘diamond of death’. When treating major haemorrhages, we should not only replace blood but also avoid and treat these factors.
The major haemorrhage protocol is activated.
After the first unit of packed red blood cells, Rhaenyra’s tachycardia slightly improves, but she remains hypotensive.
As you prepare to administer the next unit, you consider what ratio of blood products to use.
What blood product ratio should we use?
Major haemorrhage protocols typically include a mixture of packed red blood cells (pRBCs), platelets, and fresh frozen plasma (FFP). The pRBCs replace the lost red blood cells from the bleeding, carry oxygen to the tissues and also provide volume expansion to help restore blood pressure and organ perfusion. Platelets and FFP replace lost platelets and coagulation factors, which help with clotting and also provide some volume expansion.
A topic of ongoing debate is determining the optimal ratio of blood products for transfusion in the treatment of major haemorrhage. The debate is often between high/balanced ratios (≤1:1:2 ratio of one FFP: one platelet: two or fewer pRBCs) and low ratios low/ unbalanced ratios (>1:1:2 ratio of one FFP: one platelet more than two pRBCs). However, no conclusive evidence exists that a high versus a low ratio improves mortality.
The PROPPR trial, a large multicentre randomised trial in adult trauma patients, did find a significant reduction in deaths due to haemorrhage at 24 hours when high ratios (1:1:1) were given, though overall mortality was no different. Based on this trial, most adult guidelines recommend a balanced 1:1:1 ratio of FFP:platelets:pRBCs, but practice variability remains.
Studies involving children have shown mixed results regarding the data on transfusion ratios. We don’t know the best ratios for FFP:pRBCs and platelets:pRBCs in kids. A recent systematic review of pediatric patients found no clear mortality benefit for using either a high/balanced or low/unbalanced transfusion ratio. However, the studies included in the review varied widely in design and were often small, retrospective analyses, making it difficult to draw definitive conclusions. Due to the lack of strong evidence supporting a specific transfusion ratio in children, many pediatric major haemorrhage protocols align with adult guidelines, recommending a 1:1:1 ratio of fresh frozen plasma, platelets, and packed red blood cells.
In practice, achieving a balanced 1:1:1 transfusion ratio can be challenging. This is because pRBCs are often readily available, whereas FFP requires time to thaw. To address this, there is ongoing debate about whether we should consider using a whole blood transfusion approach.
Rhaenyra continues to receive blood products in a 1:1:1 ratio.
As this is being given and definitive treatment is planned (either surgery or interventional radiology), you consider what adjunctive treatments are needed.
What is the role of tranexamic acid?
In addition to blood product transfusions, tranexamic acid (TXA) is an important medication that helps reduce bleeding by preventing the breakdown of clots. TXA achieves this by impairing plasmin formation, which usually dissolves blood clots.
In adults, TXA has been shown to reduce transfusion requirements and improve outcomes. Although the use and specific dosage for paediatric major haemorrhage is unknown, a comprehensive systematic review and meta-analysis of 14 paediatric studies showed that TXA was safe in children, with no increased risk of excessive clotting. Although TXA improved outcomes in combat settings, it did not significantly improve survival in civilian settings. The TIC-TOC trial is a multicentre randomised controlled trial that explores different doses of TXA compared to placebo amongst paediatric major trauma patients. The awaited results of this study may inform our use of TXA in paediatric major haemorrhage.
Based upon the evidence of benefit amongst adults and safety in children, the Royal College of Paediatrics and Child Health (RCPCH) recommends a bolus of 15 mg/kg (maximum 1 g) TXA via a 10-minute slow infusion, followed by a 2 mg/kg/hour infusion for 8 hours. However, routine use of TXA in paediatric trauma varies worldwide.
What is the role of cryoprecipitate?
Cryoprecipitate also has a role in stabilising clot formation. Cryoprecipitate contains the clotting protein fibrinogen and other clotting factors such as factor VIII, von Willebrand factor, factor XIII, and fibronectin. These different components are often consumed in the clotting process, broken down, diluted, or lost directly from bleeding. Fibrinogen can be replaced either as one of the components in cryoprecipitate or in the form of fibrinogen concentrate. The pilot results from the Australian FEISTY multicentre randomised controlled trial compared fibrinogen concentrate with cryoprecipitate and showed that in severely injured, hypofibrinogenaemic patients, fibrinogen concentrate may be administered faster than cryoprecipitate.
It is not known whether fibrinogen replacement in the setting of traumatic major haemorrhage (whether with cryoprecipitate or fibrinogen concentrate) improves functional survival in adults or children. Currently, the first paediatric randomised controlled trial comparing fibrinogen concentrate and cryoprecipitate, FIESTY junior study is ongoing.
After Rhaenyra’s next unit of blood transfusion is complete, you get a venous blood gas.
It shows a low ionised calcium level of 0.7 mmol/L.
She is also hypothermic with a temperature of 35oc. What are yo going to do now?
What should we do about calcium?
Low calcium levels form part of the ‘diamond of death’.
Calcium is an essential co-factor for many of the components of the coagulation cascade and platelet adhesion. It can also help the blood vessels be more appropriately responsive and the heart beat more strongly. The citrate in blood products binds the active form of calcium (ionised calcium) and, therefore, is reduced when blood is transfused.
Calcium can be lower than normal due to the trauma through blood loss, binding by lactate, and other complex mechanisms. A systematic review including 1213 major adult trauma patients demonstrated low iCa was associated with increased mortality, blood transfusion requirements and coagulopathy.
In a systematic review of 710 paediatric major trauma patients, there was no significant difference in mortality. However, mortality amongst paediatric trauma patients is rare, and the review may have been underpowered to detect this. Additionally, other outcomes, such as blood transfusion requirements and haemodynamic instability, did appear to be increased amongst hypocalcaemic paediatric trauma patients.
As a result, we should consider replacing low calcium levels, however the jury is still out on the exact timing and dosage of replacement.
How do we prevent hypothermia?
Hypothermia is another part of the ‘diamond of death’. Trauma patients are at significant risk of this due to hypovolaemic shock, exposure in the primary survey, infusion of unwarmed fluids, and as a side effect of sedation and anaesthesia.
We should carefully monitor temperature and quickly address drops in temperature. Different methods can be used for rewarming. These include external rewarming using warming mattresses or radiant heaters and internal rewarming with warmed intravenous solutions.
Rhaenyra is brought to the operating theatre for further treatment, and after surgery, she is admitted to the paediatric intensive care unit.
You debrief with the team and reflect upon what you learned from managing Rhaenyra’s case.
Take Home Points
There is no agreed-upon definition for paediatric major haemorrhage, and many methods of defining it are difficult to measure in the emergency department.
Much of the evidence for the management of paediatric major haemorrhage is extrapolated from adult data; there are many paediatric studies currently ongoing.
Care must be taken to avoid the ‘diamond of death’ (coagulopathy, acidosis, hypothermia, and hypocalcemia).
Many paediatric major haemorrhage protocols recommend a balanced transfusion ratio of 1:1:1 of fresh frozen plasma:platelets:packed red blood cells.
Adjunctive treatments to prevent clot breakdown, such as tranexamic acid and cryoprecipitate/fibrinogen concentrate, should be considered.
References
Al-Jeabory M, Gasecka A, Wieczorek W, Mayer-Szary J, Jaguszewski MJ, Szarpak L. Efficacy and safety of tranexamic acid in pediatric trauma patients: Evidence from meta-analysis. Am J Emerg Med. 2021;49:404-405. doi:10.1016/j.ajem.2021.02.009
George S, Wake E, Jansen M, et al. Fibrinogen Early In Severe paediatric Trauma studY (FEISTY junior): protocol for a randomised controlled trial. BMJ Open. 2022;12(5):e057780. Published 2022 May 4. doi:10.1136/bmjopen-2021-057780
Hibberd O, Price J, Thomas SH, Harris T, Barnard EBG. The incidence of admission ionised hypocalcaemia in paediatric major trauma-A systematic review and meta-analysis. PLoS One. 2024;19(5):e0303109. Published 2024 May 28. doi:10.1371/journal.pone.0303109
Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471-482. doi:10.1001/jama.2015.12
Karageorgos S, Ren D, Ranaweera M, et al. Fifteen-minute consultation: a guide to paediatric major haemorrhage. Archives of Disease in Childhood – Education and Practice. Published Online First: 24 June 2024. doi: 10.1136/archdischild-2024-327224
Moore EE, Moore HB, Kornblith LZ, et al. Trauma-induced coagulopathy [published correction appears in Nat Rev Dis Primers. 2022 Apr 22;8(1):25. doi: 10.1038/s41572-022-00360-y]. Nat Rev Dis Primers. 2021;7(1):30. Published 2021 Apr 29. doi:10.1038/s41572-021-00264-3
Nishijima DK, VanBuren JM, Linakis SW, et al. Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC): A pilot randomized trial. Acad Emerg Med. 2022;29(7):862-873. doi:10.1111/acem.14481
Winearls J, Wullschleger M, Wake E, et al. Fibrinogen Early In Severe Trauma studY (FEISTY): results from an Australian multicentre randomised controlled pilot trial. Crit Care Resusc. 2023;23(1):32-46. Published 2023 Oct 18. doi:10.51893/2021.1.OA3
