The CRYOSTAT2 trial: The rationale and study protocol for a multi-Centre, randomised, controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage requiring major haemorrhage protocol activation

Nicola Curry¹, Ross Davenport², Joanne Lucas³, Alison Deary³, Jonathan Benger⁴, Antoinette Edwards⁵, Amy Evans³, Claire Foley³, Laura Green^{6

7}, Stephen Morris⁸, Helen Thomas⁹, Karim Brohi², Simon J Stanworth¹⁰

Affiliations

¹ Oxford UniversityHospitals NHS Foundation Trust, Nuffield Orthopaedic Hospital, Oxford, UK.
² Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, London, UK.
³ NHS Blood and Transplant Clinical Trials Unit, Cambridge, UK.
⁴ Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK.
⁵ Trauma Audit and Research Network, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK.
⁶ Blizard Institute, Queen Mary University of London, London, UK.
⁷ NHS Blood and Transplant and Bart's Health NHS Trust, London, UK.
⁸ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁹ NHS Blood and Transplant Clinical Trials Unit, Bristol, UK.
¹⁰ NHS Blood and Transplant and Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.

PMID: 36321753
DOI: 10.1111/tme.12932

The CRYOSTAT2 trial: The rationale and study protocol for a multi-Centre, randomised, controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage requiring major haemorrhage protocol activation

Nicola Curry et al. Transfus Med. 2023 Apr.

. 2023 Apr;33(2):123-131.

doi: 10.1111/tme.12932. Epub 2022 Nov 2.

Authors

Affiliations

¹ Oxford UniversityHospitals NHS Foundation Trust, Nuffield Orthopaedic Hospital, Oxford, UK.
² Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, London, UK.
³ NHS Blood and Transplant Clinical Trials Unit, Cambridge, UK.
⁴ Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK.
⁵ Trauma Audit and Research Network, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, UK.
⁶ Blizard Institute, Queen Mary University of London, London, UK.
⁷ NHS Blood and Transplant and Bart's Health NHS Trust, London, UK.
⁸ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁹ NHS Blood and Transplant Clinical Trials Unit, Bristol, UK.
¹⁰ NHS Blood and Transplant and Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.

PMID: 36321753
DOI: 10.1111/tme.12932

Abstract

Objectives: To describe the protocol for a multinational randomised, parallel, superiority trial, in which patients were randomised to receive early high-dose cryoprecipitate in addition to standard major haemorrhage protocol (MHP), or Standard MHP alone.

Background: Blood transfusion support for trauma-related major bleeding includes red cells, plasma and platelets. The role of concentrated sources of fibrinogen is less clear and has not been evaluated in large clinical trials. Fibrinogen is a key pro-coagulant factor that is essential for stable clot formation. A pilot trial had demonstrated that it was feasible to deliver cryoprecipitate as a source of fibrinogen within 90 min of admission.

Methods: Randomisation was via opaque sealed envelopes held securely in participating Emergency Departments or transfusion laboratories. Early cryoprecipitate, provided as 3 pools (equivalent to 15 single units of cryoprecipitate or 6 g fibrinogen supplementation), was transfused as rapidly as possible, and started within 90 min of admission. Participants in both arms received standard treatment defined in the receiving hospital MHP. The primary outcome measure was all-cause mortality at 28 days. Symptomatic thrombotic events including venous thromboembolism and arterial thrombotic events (myocardial infarction, stroke) were collected from randomisation up to day 28 or discharge from hospital. EQ5D-5Land Glasgow Outcome Score were completed at discharge and 6 months. All analyses will be performed on an intention to treat basis, with per protocol sensitivity analysis.

Results: The trial opened for recruitment in June 2017 and the final patient completed follow-up in May 2022.

Discussion: This trial will provide firmer evidence to evaluate the effectiveness and cost-effectiveness of early high-dose cryoprecipitate alongside the standard MHP in major traumatic haemorrhage.

Keywords: Haemorrhage; cryoprecipitate; fibrinogen; transfusion; trauma.

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References

REFERENCES

1. World Health Organization (WHO). Injuries and violence. WHO; 2021. https://www.who.int/news-room/fact-sheets/detail/injuries-and-violence
1. World Health Organization (WHO). Road traffic injuries; 2021. https://www.who.int/news-room/fact-sheets/detail/road-traffic-injuries
1. NIHR PGfAR 10036: Traumatic Coagulopathy and Massive Transfusion: Improving outcomes and saving blood. https://fundingawards.nihr.ac.uk/award/RP-PG-0407-10036
1. Campbell HE, Stokes EA, Bargo DN, et al. Quantifying the healthcare costs of treating severely bleeding major trauma patients: a national study for England. Crit Care. 2015;19(1):276.
1. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma. 2003;54(6):1127-1130.

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The CRYOSTAT2 trial: The rationale and study protocol for a multi-Centre, randomised, controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage requiring major haemorrhage protocol activation

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The CRYOSTAT2 trial: The rationale and study protocol for a multi-Centre, randomised, controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage requiring major haemorrhage protocol activation

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