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Background

Background

Introduction: For people at ages 5 to 45 years, trauma is second only to HIV/AIDS as a cause of death. Each year, worldwide, about three million people die as a result of trauma, many after reaching hospital.[ref 1] Among trauma patients who do survive to reach hospital, exsanguination is a common cause of death, accounting for nearly half of in-hospital trauma deaths.[ref 2] Central nervous system injury and multi-organ failure account for most of the remainder, both of which can be exacerbated by severe bleeding.[ref 3]

Mechanisms: The haemostatic system helps to maintain the integrity of the circulatory system after severe vascular injury, whether traumatic or surgical in origin.[ref 4] Major surgery and trauma trigger similar haemostatic responses and the consequent massive blood loss presents an extreme challenge to the coagulation system. Part of the response to surgery and trauma, in any patient, is stimulation of clot breakdown (fibrinolysis) which may become pathological (hyper-fibrinolysis) in some.[ref 4] Antifibrinolytic agents have been shown to reduce blood loss in patients with both normal and exaggerated fibrinolytic responses to surgery, and do so without apparently increasing the risk of post-operative complications, most notably there is no increased risk of venous thromboembolism.[ref 5]

Existing knowledge: Systemic antifibrinolytic agents are widely used in major surgery to prevent fibrinolysis and thus reduce surgical blood loss. A recent systematic review [ref 6] of randomised controlled trials of antifibrinolytic agents (mainly aprotinin or tranexamic acid) in elective surgical patients identified 89 trials including 8,580 randomised patients (74 trials in cardiac, eight in orthopaedic, four in liver, and three in vascular surgery). The results showed that these treatments reduced the numbers needing transfusion by one third, reduced the volume needed per transfusion by one unit, and halved the need for further surgery to control bleeding. These differences were all highly statistically significant. There was also a statistically non-significant reduction in the risk of death (RR=0.85: 95% CI 0.63 to 1.14) in the antifibrinolytic treated group.
Hypothesis: Because the coagulation abnormalities that occur after injury are similar to those after surgery, it is possible that antifibrinolytic agents might also reduce blood loss, the need for transfusion and mortality following trauma. However, to date there has been only one small randomised controlled trial (70 randomised patients, drug versus placebo: 0 versus 3 deaths) of the effect of antifibrinolytic agents in major trauma.[ref 7] As a result, there is insufficient evidence to either support or refute a clinically important treatment effect. Systemic antifibrinolytic agents have been used in the management of eye injuries where there is some evidence that they reduce the rate of secondary haemorrhage.[ref 8]
Need for a trial: A simple and widely practicable treatment that reduces blood loss following trauma might prevent thousands of premature trauma deaths each year and secondly could reduce exposure to the risks of blood transfusion. Blood is a scarce and expensive resource and major concerns remain about the risk of transfusion-transmitted infection. Trauma is common in parts of the world where the safety of blood transfusion is not assured. A recent study in Uganda estimated the population-attributable fraction of HIV acquisition as a result of blood transfusion to be around 2%, although some estimates are much higher.[ref 9],[ref 10] Only 43% of the 191 WHO member states test blood for HIV and hepatitis C and B viruses. Every year unsafe transfusion and injection practices are estimated to account for 8-16 million Hepatitis B infections, 2.3-4.7 million Hepatitis C infections and 80,000-160,000 HIV infections.[ref 11] A large randomised trial is therefore needed of the use of a simple, inexpensive, widely practicable antifibrinolytic treatment such as tranexamic acid (aprotinin is considerably more expensive and is a bovine product with consequent risk of allergic reaction and hypothetically transmission of disease), in a wide range of trauma patients who, when they reach hospital are thought to be at risk of major haemorrhage that could significantly affect their chances of survival.
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Dose Selection

The systematic review of randomised controlled trials of antifibrinolytic agents in surgery showed that dose regimens of tranexamic acid vary widely.[ref 6] Loading doses range from 2.5mg/kg to 100 mg/kg and maintenance doses from 0.25 mg/kg/hr to 4 mg/kg/hr delivered over time periods of one to twelve hours. Studies examining the impact of different doses of tranexamic acid on bleeding and transfusion requirements showed no significant difference between a high dose and a low dose.

Studies in cardiac surgery have shown that a 10 mg/kg initial dose of tranexamic acid followed by an infusion of 1 mg/kg/hour produces plasma concentrations sufficient to inhibit fibrinolysis in vitro.[ref 12] The dose-response relationship of tranexamic acid was examined by Horrow et al (1995) who concluded that 10 mg/kg followed by 1 mg/kg/hour decreases bleeding after extracorporeal circulation and that larger doses did not provide any additional haemostatic benefit.[ref 13]
In this emergency situation, administration of a fixed dose would be more practicable as determining the weight of a patient would be impossible. Therefore a fixed dose within the dose range which has been shown to inhibit fibrinolysis and provide haemostatic benefit is being used for this trial. The fixed dose chosen would be efficacious for larger patients (>100 kgs) but also safe in smaller patients (<50 kgs), as the estimated dose/kg the latter group would receive has been applied in other trials without adverse effects. The planned duration of administration allows for the full effect of tranexamic acid on the immediate risk of haemorrhage without extending too far into the acute phase response seen after surgery and trauma.

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