Background: Traumatic haemorrhage is common after severe injury, leading to disability and death. Cryoprecipitate, a source of fibrinogen, may improve outcomes for patients with traumatic haemorrhage.
Objective: To investigate the effects of early fibrinogen supplementation in the form of 3 pools (15 units, approximately 6 g of fibrinogen) of cryoprecipitate on 28-day mortality.
Design: A randomised, parallel-group, unblinded, multicentre, international trial and economic evaluation. Patients were randomised to either the intervention (early cryoprecipitate) or the comparator (standard major haemorrhage protocol) arm via opaque, sealed envelopes in the emergency department or the transfusion laboratory/blood bank. All analyses were performed on an intention-to-treat basis. A cost-effectiveness analysis was undertaken.
Setting: Twenty-five major trauma centres in the UK and one level 1 trauma centre in the USA.
Participants: Adults who had traumatic haemorrhage following severe injury requiring activation of the major haemorrhage protocol and had received a blood transfusion.
Intervention: Early cryoprecipitate - 3 pools (equivalent to 15 single units of cryoprecipitate or 6 g of fibrinogen supplementation), infused as rapidly as possible, within 90 minutes of arrival at hospital in addition to standard major haemorrhage protocol or standard major haemorrhage protocol only.
Main outcome measures: The primary outcome was all-cause mortality at 28 days. The secondary outcomes were all-cause mortality at 6 hours, 24 hours, 6 months and 12 months from admission; death from bleeding at 6 hours and 24 hours; transfusion requirements at 24 hours from admission; destination of participant at discharge; quality-of-life measurements (EuroQol-5 Dimensions, five-level version and Glasgow Outcome Scale) at discharge/day 28 and 6 months after injury; and hospital resource use up to discharge or day 28 (including ventilator-days, hours spent in critical care and inpatient stays).
Results: Eight hundred and five patients were randomised to receive the standard major haemorrhage protocol (control arm). Seven hundred and ninety-nine patients were randomised to receive an additional three pools of cryoprecipitate in addition to standard care (intervention arm). Baseline characteristics appeared well matched. Patients had a median age of 39 (interquartile range 26-55) years, and the majority (79%) were male. All-cause 28-day mortality (n = 1531 patients; intention to treat) was 25.3% in the intervention arm compared with 26.1% in the control arm (odds ratio 0.96; p = 0.74).
Limitations: There was variability in the timing of cryoprecipitate administration, with overlap between the treatment arms, limiting the degree of intervention separation.
Conclusions: There was no evidence that early empiric administration of high-dose cryoprecipitate reduced the risk of death in unselected patients with traumatic haemorrhage. There was also no difference in adverse events. The cost-effectiveness of the intervention was similar to that of standard care.
Future work: Research to evaluate if fibrinogen replacement is more beneficial for selected patients, for example those with low fibrinogen blood levels, is needed, as is further exploration of whether there is a difference in outcome according to mechanism of injury.
Trial registration: This trial is registered as ISRCTN14998314.
Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/57/02) and is published in full in Health Technology Assessment; Vol. 28, No. 76. See the NIHR Funding and Awards website for further award information.
Keywords: ADULTS; BLEEDING; CLINICAL TRIAL; FIBRINOGEN; MORTALITY; TRAUMA.
Uncontrolled bleeding following injury is a leading cause of death and disability, killing over 12,000 people in the United Kingdom every year. People who have severe bleeding after injury often develop a problem with their clotting system that means that they tend to bleed more. One change after trauma is low levels of fibrinogen, a clotting protein normally circulating in the bloodstream. Fibrinogen acts as the ‘glue’ that holds a blood clot together. At low levels, blood clots do not form properly, and bleeding can continue. Cryoprecipitate is stored as a frozen type of blood component that is prepared from plasma after blood donation. It is rich in fibrinogen. This study investigated whether giving a high dose of cryoprecipitate transfusion as soon as possible after injury reduced death rates. We studied people who required a blood transfusion following major injury due to trauma admitted at 26 hospitals in the United Kingdom and the United States of America. A total of 1604 people were allocated at random to one of two study groups. One group were given an early transfusion of high-dose cryoprecipitate in addition to standard treatments including other blood transfusions. The other group received the standard treatment alone. Outcomes from 1531 participants were analysed. Among participants treated with the additional early cryoprecipitate, the death rate was 25.3% (192/760). In the standard treatment group, the death rate was 26.1% (201/771). There was no evidence that treating patients with early high-dose cryoprecipitate had an effect on the death rate. There were also no differences in side effects. The economic analysis shows that, overall, treatment costs and quality of life did not differ between patients who received early cryoprecipitate and patients who did not.