Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury: The CRYOSTAT-2 Randomized Clinical Trial

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]; P = .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.

Figure 1.. Flow of Participants in CRYOSTAT-2

^aThe trauma team leader assessed the patient to confirm whether the participant was 16 years or older either by information known to the team or by visual inspection; sustained severe injury; was bleeding (using a combination of vital signs/clinical inspection and examination) and needed transfusion therapy according to the major hemorrhage protocol; and had/or was receiving 1 U of any blood component. ^bIf the age of a participant was not known at randomization, eligibility was fulfilled if the trauma team leader judged the participant to be 16 years or older. ^cIncluded pregnancy, local policy exclusions, and patient in police custody. ^dIncluded COVID-19, out of hours, research team not contacted, study closed, and rushed to surgery. ^eAn additional 3 pools of cryoprecipitate delivered as early as possible and starting within 90 minutes of admission were added to the standard care. ^fStandard major hemorrhage protocols delivered red blood cells and fresh frozen plasma in 4×4 unit packs, with a pool of platelets and 2 pools of cryoprecipitate in the second and subsequent packs.

Figure 2.. Mortality Overall and by Injury Type

The median number of days observed was 28 days for all groups. Mortality at day 28 was analyzed as a binary outcome with odds ratios, 95% CIs, and P values reported in the results and in Figure 3.

Figure 3.. Primary Outcome Analyses of All-Cause Mortality by 28 Days

^aP value for treatment group term in mixed logistic regression model, adjusted for center. ^bP value for interaction term between subgroup and treatment group in a mixed logistic regression model, adjusted for center, subgroup and treatment group. ^cThe Abbreviated Injury Scale (AIS) is a severity scoring system that categorizes injury by body region using a 6-point score. A score of 1 describes minor injury and a score of 6 maximal injury. An AIS score of 4 or more defines severe injury. ^dP value for treatment group term in an unadjusted logistic regression model.