LATIN AMERICA & CARIBBEAN

Six month follow-up is, of course, on-going and we aim to achieve the same high levels of follow-up that were achieved with the early outcome data. It will be hard work but on the basis of experience to date there is absolutely no reason to doubt that this will be successful. A second paper will then be prepared presenting the effect of corticosteroids on death and disability. This is, of course, every bit as important as (and many would argue more important than) determining the effect on in-hospital mortality. The Co-ordinating Centre in London will do everything it can to support you with six month follow-up.

Many collaborators have asked the question …so what next? In answering the corticosteroid question we have built up a fantastic network of collaboration, one that is built on trust and mutual respect. The collaboration has shown that it can randomise very large numbers of patients in the emergency setting and achieve excellent levels of data completeness. It would be a tragedy and a waste if this wonderful global network of collaboration was now scattered to the winds. Well, there is good news! Over the past six months there has been a lot of work on the plans for CRASH 2 and further details are provided in this newsletter. The protocol for CRASH 2 was recently considered by World Health Organisation. They are “strongly supportive that the CRASH 2 trial move forward” and will provide some financial support. CRASH 2 is coming and we very much hope that we can continue to work with you.

The haemostatic system mounts a similar response to maintain the integrity of the circulatory system after severe vascular injury, whether the cause is traumatic or surgical.[ref 4] Any 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 fibrinolysis (clot breakdown) 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. Moreover, there is no apparent increased risk of venous thromboembolism.[ref 5]

Systemic antifibrinolytic agents are widely used in major surgery to 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.

The haemostatic changes after injury are similar to those after surgery, and thus it seems logical to test the hypothesis that antifibrinolytic agents may 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]

It is important to investigate a simple and widely practicable treatment that might reduce blood loss following trauma, for worldwide it 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. Indeed, 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. To this end a large international placebo controlled trial of the effects of the early administration of the antifibrinolytic agent tranexamic acid on death, vascular events and transfusion requirements has been designed.[ref 12] Known as CRASH 2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage), this trial aims to recruit some 20,000 patients with trauma and will be one of the largest trauma trials ever conducted. However, it will only be possible to conduct such a trial if hundreds of health care professionals in emergency care join the trial; we very much hope for your support.

REFERENCES
1. Murray CJL, Lopez AD. Global health statistics: a compendium of incidence, prevalence and mortality estimates for over 200 conditions. Harvard School of Public Health, Boston: Harvard University Press, 1996.

2. Sauaia A, Moore FA, Moore E, Moser K, Brennan R, Read RA, Pons PT. Epidemiology of trauma deaths: a reassessment. J Trauma1995;38:185-193.

3. The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Hypotension. J Neurotrauma. 2000;17(6-7):591-5.

4. Lawson JH, Murphy MP. Challenges for providing effective hemostasis in surgery and trauma. Semin Hematol 2004;41:55-64.

5. Porte RJ, Leebeek FW. Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery. Drugs 2002; 62: 2193-211.

6. Henry DA, Moxey AJ, Carless PA, O'Connell D, McClelland B, Henderson KM, Sly K, Laupacis A, Fergusson D. Antifibrinolytic use for minimising perioperative allogeneic blood transfusion (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.

7. Coats T, Roberts I, Shakur H. Antifibrinolytic drugs for acute traumatic injury. (Cochrane Review). In: The Cochrane Library, Issue 3, 2004. Chichester, UK: John Wiley & Sons, Ltd.

8. Aylward GW, Dunlop IS, Little BC. Meta-analysis of systemic antifibrinolytics in traumatic hyphema. Eye 1994;8:440-442.

9. Kiwanuka N, Gray RH, Serwadda D, et al. The incidence of HIV-1 associated with injections and transfusions in a prospective cohort, Raki, Uganda. AIDS 2004;18:342-343.

10. Heymann SJ, Brewer TF. The problem of transfusion associated acquired immunodeficiency syndrome in Africa: a quantitative approach. Am J Infection Control 1992;20:256-62.

11. Goodnough LT, Shander A, Brecher ME. Transfusion medicine: looking to the future. Lancet 2003; 361: 161-9.

12. WWW.CRASH2.LSHTM.AC.UK

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