Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury

Abstract

ImportanceCritical 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.ObjectiveTo 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 ParticipantsCRYOSTAT-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.InterventionPatients 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 MeasuresThe primary outcome was all-cause mortality at 28 days in the intention-to-treat population.ResultsAmong 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT04704869; ISRCTN Identifier: ISRCTN14998314

Does an early, balanced resuscitation strategy reduce the incidence of hypofibrinogenemia in hemorrhagic shock?

“…The recently published CRYOSTAT-2 (Early Cryoprecipitate in Major Trauma Hemorrhage) Study randomized patients to standard resuscitation practices or standard practices plus empiric cryoprecipitate transfusion. 22 In this trial, no clinical benefit was seen in patients randomized to empiric transfusion. It is noteworthy that the median time from admission to first administration of cryoprecipitate was 68 min, with less than 70% of the intervention arm patients receiving cryoprecipitate within the study goal of 90 minutes from admission.…”

Outcomes of Patients Enrolled in a Prospective and Randomized Trial on Basis of Gestalt Assessment or ABC Score

“…Although PROPPR was conducted some time ago, trauma resuscitation continues to be an area of active research. There have been several large and important randomized trauma transfusion clinical trials since PROPPR, including the Prehospital Air Medical Plasma (PAMPer), 11 Control of Major Bleeding After Trauma (COMBAT), 12 Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage-2 (CRASH-2), 13 CRYOSTAT-2, 14 and several more are currently in progress including Trauma Resuscitation With Low-Titer Group O Whole Blood or Products, 10 Trauma and Prothrombin Complex Concentrate 15 and type O whole blood and assessment of AGE during prehospital Resuscitation 16 trials. Rapid and accurate selection of patients for these regulated trials is of paramount importance, and critical to their success.…”

Research priorities for the management of major trauma: an international priority setting partnership with the James Lind Alliance

“…Over time, barriers to conducting high-quality research in emergency settings have been progressively addressed, including the implementation of exceptions from informed consent for emergency research and the incorporation of novel study designs. 9 10 Nevertheless, international teams aiming to address these priorities are likely to need to secure funding from various organisations and navigate diverse regulatory frameworks. Despite these challenges, this priority-setting exercise has set a definitive, patient-centred tone, providing a road map for researchers to enhance the treatment and outcomes for patients following major traumatic injuries.…”

“… 4 8 More recently, several international randomised controlled trials have been conducted and reported, evaluating interventions for the most severely injured patients in highly acute treatment settings. 9 10 These demonstrate that high-quality research in major trauma is feasible and effective, but qualitative research suggests contemporary studies may not encompass topics and outcomes valued by trauma patients. 11 There is now an urgent need to identify research priorities to ensure that funding and resources are directed towards areas deemed most important by trauma patients and their families.…”