1.
Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury: The CRYOSTAT-2 Randomized Clinical Trial
Davenport, R., Curry, N., Fox, E. E., Thomas, H., Lucas, J., Evans, A., Shanmugaranjan, S., Sharma, R., Deary, A., Edwards, A., et al
Jama. 2023
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Editor's Choice
Abstract
IMPORTANCE Critical bleeding is associated with a high mortality rate in patients with trauma. Hemorrhage is exacerbated by a complex derangement of coagulation, including an acute fibrinogen deficiency. Management is fibrinogen replacement with cryoprecipitate transfusions or fibrinogen concentrate, usually administered relatively late during hemorrhage. OBJECTIVE To assess whether survival could be improved by administering an early and empirical high dose of cryoprecipitate to all patients with trauma and bleeding that required activation of a major hemorrhage protocol. DESIGN, SETTING, AND PARTICIPANTS CRYOSTAT-2 was an interventional, randomized, open-label, parallel-group controlled, international, multicenter study. Patients were enrolled at 26 UK and US major trauma centers from August 2017 to November 2021. Eligible patients were injured adults requiring activation of the hospital's major hemorrhage protocol with evidence of active hemorrhage, systolic blood pressure less than 90 mm Hg at any time, and receiving at least 1 U of a blood component transfusion. INTERVENTION Patients were randomly assigned (in a 1:1 ratio) to receive standard care, which was the local major hemorrhage protocol (reviewed for guideline adherence), or cryoprecipitate, in which 3 pools of cryoprecipitate (6-g fibrinogen equivalent) were to be administered in addition to standard care within 90 minutes of randomization and 3 hours of injury. MAIN OUTCOMES AND MEASURES The primary outcome was all-cause mortality at 28 days in the intention-to-treat population. RESULTS Among 1604 eligible patients, 799 were randomized to the cryoprecipitate group and 805 to the standard care group. Missing primary outcome data occurred in 73 patients (principally due to withdrawal of consent) and 1531 (95%) were included in the primary analysis population. The median (IQR) age of participants was 39 (26-55) years, 1251 (79%) were men, median (IQR) Injury Severity Score was 29 (18-43), 36% had penetrating injury, and 33% had systolic blood pressure less than 90 mm Hg at hospital arrival. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs 25.3% in the cryoprecipitate group (odds ratio, 0.96 [95% CI, 0.75-1.23]; Pā=ā.74). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs cryoprecipitate group (12.9% vs 12.7%). CONCLUSIONS AND RELEVANCE Among patients with trauma and bleeding who required activation of a major hemorrhage protocol, the addition of early and empirical high-dose cryoprecipitate to standard care did not improve all cause 28-day mortality. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04704869; ISRCTN Identifier: ISRCTN14998314.
PICO Summary
Population
Bleeding patients with trauma enrolled in the CRYOSTAT-2 trial, at 26 UK and US major trauma centers (n= 1,604).
Intervention
Usual care plus 3 early pools of cryoprecipitate (n= 799).
Comparison
Standard care (n= 805).
Outcome
The primary outcome was all-cause mortality at 28 days in the intention-to-treat population. Data from 1,531 (95%) patients were included in the primary analysis population. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs. 25.3% in the cryoprecipitate group (odds ratio, 0.96; 95% CI [0.75, 1.23]). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs. cryoprecipitate group (12.9% vs. 12.7%).
2.
Empiric Cryoprecipitate Transfusion in Patients with Severe Hemorrhage: Results from The US Experience in the International Cryostat-2 Trial
Van Gent, J. M., Kaminski, C. W., Praestholm, C., Pivalizza, E. G., Clements, T. W., Kao, L. S., Stanworth, S., Brohi, K., Cotton, B. A.
Journal of the American College of Surgeons. 2023
Abstract
BACKGROUND Hypofibrinogenemia has been shown to predict massive transfusion and is associated with higher mortality in severely injured patients. However, the role of empiric fibrinogen replacement in bleeding trauma patients remains controversial. We sought to determine the effect of empiric cryoprecipitate as an adjunct to a balanced transfusion strategy (1:1:1). STUDY DESIGN Sub-analysis of the single US trauma center in a multi-center randomized controlled trial. Trauma patients (>15 years of age) were eligible if they had evidence of active hemorrhage requiring emergent surgery or interventional radiology, massive transfusion protocol (MTP) activation, and received at least one unit of blood. Transfer patients, those with injuries incompatible with life, or >3 hours from injury were excluded. Patients were randomized to standard MTP (STANDARD) or MTP plus 3 pools of cryoprecipitate (CRYO). Primary outcome: all-cause mortality at 28 days. Secondary outcomes: transfusion requirements, intra-operative and post-operative coagulation labs, and quality of life measures (Glasgow Outcome Score, GOS). RESULTS 49 patients were enrolled between 05/21-10/21 (CRYO-23 and STANDARD-26). Time to randomization was similar between groups (14 minutes vs 24 minutes); p=0.676. Median time to cryoprecipitate was 52 minutes [IQR, 47,60]. There were no differences in demographics, arrival physiology, laboratory values, or injury severity. Intra-operative and ICU TEG values, including functional fibrinogen, were similar between groups. There was no benefit to CRYO with respect to post-ED transfusions (intra-op and ICU through 24 hours), complications, GOS, or mortality. CONCLUSION In this study of severely injured, bleeding trauma patients, empiric cryoprecipitate did not improve survival or reduce transfusion requirements. Cryoprecipitate should continue as an "on demand" addition to a balanced transfusion strategy, guided by laboratory values and should not be given empirically.
3.
Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial
Curry N, Rourke C, Davenport R, Beer S, Pankhurst L, DearyA, Thomas H, Llewelyn C, Green L, Doughty H, et al
British Journal of Anaesthesia. 2015;115((1)):76-83.
Abstract
BACKGROUND Low fibrinogen (Fg) concentrations in trauma haemorrhage are associated with poorer outcomes. Cryoprecipitate is the standard source for Fg administration in the UK and USA and is often given in the later stages of transfusion therapy. It is not known whether early cryoprecipitate therapy improves clinical outcomes. The primary aim of this feasibility study was to determine whether it was possible to administer cryoprecipitate, within 90 min of admission to hospital. Secondary aims were to evaluate laboratory measures of Fg and clinical outcomes including thrombotic events, organ failure, length of hospital stay and mortality. METHODS This was an unblinded RCT, conducted at two civilian UK major trauma centres of adult trauma patients (age >16 yrs), with active bleeding and requiring activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy (STANDARD) (n=22), or to standard haemorrhage therapy plus two early pools of cryoprecipitate (CRYO) (n=21). RESULTS 85% (95% CI: 69-100%) CRYO participants received cryoprecipitate within 90 min, median time 60 min (IQR: 57-76) compared with 108 min (67-147), CRYO and STANDARD arms respectively (P=0.002). Fg concentrations were higher in the CRYO arm and were maintained above 1.8 g litre(-1) at all time-points during active haemorrhage. All-cause mortality at 28 days was not significantly different (P=0.14). CONCLUSIONS Early Fg supplementation using cryoprecipitate is feasible in trauma patients. This study supports the need for a definitive RCT to determine the effect of early Fg supplementation on mortality and other clinical outcomes. TRIAL REGISTRY NUMBER ISRCTN55509212.Copyright © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.