PROTOCOL |
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. |
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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