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Fibrinogen Early In Severe Trauma studY (FEISTY): results from an Australian multicentre randomised controlled pilot trial
James Winearls, Martin Wullschleger, Elizabeth Wake, Zoe McQuilten, Michael Reade, Catherine Hurn, Glenn Ryan, Melita Trout, James Walsham, Anthony Holley, Shane George, Wayne Dyer, James McCullough, Gerben Keijzers, John Fraser, Jeffrey Presneill, Don Campbell
Crit Care Resusc 2021; 23 (1): 32-46
- James Winearls 1, 2, 3, 4
- Martin Wullschleger 5
- Elizabeth Wake 5
- Zoe McQuilten 6, 7
- Michael Reade 8, 9, 10
- Catherine Hurn 2, 10
- Glenn Ryan 2, 11
- Melita Trout 12, 13
- James Walsham 2, 11
- Anthony Holley 2, 10
- Shane George 2, 14, 15
- Wayne Dyer 16
- James McCullough 1
- Gerben Keijzers 1, 3, 17
- John Fraser 2, 18
- Jeffrey Presneill 19, 20
- Don Campbell 5
James Winearls has received educational, travel and research support from Werfen, Haemonetics and CSL Behring. Shane George has received research support for FEISTY Junior from Werfen, Haemonetics and CSL Behring.
BACKGROUND: Haemorrhage is a major cause of death in severe trauma. Fibrinogen plays a critical role in maintaining haemostasis in traumatic haemorrhage, and early replacement using fibrinogen concentrate (FC) or cryoprecipitate (Cryo) is recommended by several international trauma guidelines. Limited evidence supports one product over the other, with widespread geographic and institutional variation in practice. Two previous trials have investigated the feasibility of rapid FC administration in severely injured trauma patients, with conflicting results.
OBJECTIVE: To compare the time to fibrinogen replacement using FC or Cryo in severely injured trauma patients with major haemorrhage and hypofibrinogenaemia.
DESIGN, SETTING, PATIENTS AND INTERVENTIONS: A multicentre controlled pilot trial in which adult trauma patients with haemorrhage were randomly assigned (1:1) to receive FC or Cryo for fibrinogen replacement, guided by FIBTEM A5 (functional fibrinogen assessment at 5 minutes after clot formation, using rotational thromboelastometry).
MAIN OUTCOME MEASURES: The primary outcome was time to commencement of fibrinogen replacement. Secondary outcomes included effects of the intervention on plasma fibrinogen levels and clinical outcomes including transfusion requirements and mortality.
RESULTS: Of the 100 randomly assigned patients, 62 were hypofibrinogenaemic and received the intervention (n = 37) or Cryo (n = 25). Median (interquartile range [IQR]) time to delivery of FC was 29 min (23–40 min) compared with 60 min (40–80 min) for Cryo (P = 0.0001). All 62 patients were hypofibrinogenaemic before receiving FC or Cryo (FC: median FIBTEM A5, 8 mm [IQR, 7–9 mm]; Cryo: median FIBTEM A5, 9 mm [IQR, 5–10 mm]). In the FC arm patients received a median of 3 g FC (IQR, 2–4 g), and in the Cryo arm patients received a median of 8 units of Cryo (IQR, 8–14 units). Restoration of fibrinogen levels was achieved in both arms after the intervention. Blood product transfusion, fluid resuscitation and thromboembolic complications were similar in both arms. Overall mortality was 15.3%, with more deaths in the FC arm.
CONCLUSION: Fibrinogen replacement in severely injured trauma patients with major haemorrhage and hypofibrinogenaemia was achieved substantially faster using FC compared with Cryo. Fibrinogen levels increased appropriately using either product. The optimal method for replacing fibrinogen in traumatic haemorrhage is controversial. Our results will inform the design of a larger trial powered to assess patient-centred outcomes.
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Fibrinogen plays a critical role in maintaining effective haemostasis in traumatic haemorrhage and TIC. 8, 9, 10, 11
Fibrinogen can be replaced with fresh frozen plasma (FFP), cryoprecipitate (Cryo) or fibrinogen concentrate (FC), which contain different concentrations of fibrinogen (2 g/L, 8–16 g/L and 20 g/L, respectively). The low concentration of fibrinogen in FFP and the large volumes required potentially make FFP unsuitable for dedicated fibrinogen replacement. 22, 23, 24
Several key questions regarding fibrinogen replacement in traumatic haemorrhage remain unanswered, including:
- What tests, if any, should be used to guide fibrinogen replacement?
- What is the optimal product for fibrinogen replacement?
- What is the optimal dose of fibrinogen?
- What is the impact of early fibrinogen replacement on clinically important outcomes?
Eligibility criteria and randomisation
Patients were randomly assigned to an intervention arm (1:1) using a block randomisation schedule produced by a statistician independent to the study, accommodating the possibility of unequal patient recruitment across the four sites. Secure, password-protected, web-based randomisation occurred on patient arrival to the trauma unit. Patients subsequently received protocol-directed FC or Cryo replacement. Allocation concealment was maintained through to the conclusion of the web-based randomisation process but, for practical and safety reasons, patients and their treating health care professionals were not blinded to the trial intervention. Trial integrity was supported by maintenance of blinding for outcome assessors and the trial statistician.
Ethics approval and consent to participate
All other care received by trial patients was prescribed by the treating clinicians according to relevant local hospital clinical and trauma guidelines, based on the principles of damage control resuscitation.
Sample and data collection
Sample size and statistical analysis
Baseline variables were summarised using descriptive statistics. The primary outcome and other time-to-event outcomes are displayed as Kaplan–Meier curves, compared between treatments using a log-rank test, and summarised using the Kaplan–Meier estimated median time to event. 34
An independent data and safety monitoring committee (DSMC) blinded to the randomisation data monitored results of the trial and patient safety data. All serious adverse events were evaluated and classified independently by the co-chief investigators, and any disagreements were resolved by consensus. The DSMC planned to conduct two equally spaced interim analyses, at one-third (n = 33) and two-thirds (n = 67) of recruitment, to assess the differential proportions of all-cause hospital mortality (censored at 30 days for practical reasons). These interim analyses followed a group sequential plan employing symmetrical, two-sided, Haybittle–Peto three-standard-deviation thresholds to evaluate a standardised test statistic (|Zk| ≥ 3) calculated from a normal approximation to the discrete binomial difference observed between treatment and control groups in mortality. In practice, the trial recruited rapidly, with the first 30-day follow-up interim analysis being the only one completed and reviewed by the DSMC before recruitment completion. The manuscript was produced according to CONSORT recommendations for reporting randomised clinical trials.
Recruitment and patient characteristics
Patients were randomised into the trial based on clinical evidence or suspicion of major active haemorrhage, but only received fibrinogen replacement if deemed hypofibrinogenaemic by a pre-defined FIBTEM A5 value. Of the 98 patients included in the final analysis, 62 patients required fibrinogen replacement at some point during their hospital admission (FC, n = 37; Cryo, n = 25).
Baseline patient characteristics are shown in Table 1. Patients were significantly injured (mean ISS, 26) and predominantly men with a blunt mechanism of injury. The arms were well matched at baseline in terms of haemodynamic parameters and ISS. However, patients in the FC arm potentially had worse neurological status at baseline (lowest pre-hospital median GCS, 3 v 12), and a larger proportion of them required pre-hospital intubation. Pre-hospital highest GCS was lower in the FC arm (median, 12 v 15). In addition, the mean abbreviated injury scale (AIS) score for head and neck was worse in the FC arm compared with the Cryo arm (mean, 1.8 v 1.4), and a greater proportion of patients in the Cryo arm scored zero for head and neck AIS compared with those in the FC arm (64% [16/25] v 49% [18/37]). The arms were well matched in terms of baseline laboratory values (Table 2).
The administration of fibrinogen products was rapid; the median (IQR) duration of FC administration was 4 (2–8) min, compared with 12.5 (8–24) min for Cryo. In the FC arm, the median FIBTEM A5 was 8 mm (IQR, 7–9 mm) with patients receiving a median of 3 g FC (IQR, 2–4 g). In the Cryo arm, the median FIBTEM A5 was 9 mm (IQR, 5–10 mm) with patients receiving a median of 8 units of Cryo (IQR, 8–14 units).
Across the whole cohort, patients received a median of 3.16 L of crystalloid fluid resuscitation in the first 24 h after injury. There was no suggestion that patients assigned to the FC arm received more crystalloid or colloid fluid at any stage of resuscitation up to 24 h after injury (Table 4).
Fibrinogen levels incremented appropriately after both FC and Cryo administration (Table 5). In a linear model using a generalised estimating equation approach to account for clustering of pre-treatment and post-treatment results within individual patients (and also using robust error calculations), strong evidence was found of a greater FIBTEM A5 in the first test after Cryo compared with before treatment (mean difference, 2.4 mm; 95% CI, 1.1–3.7 mm; P < 0.0005). There was also strong evidence that FC treatment was associated with an elevation of FIBTEM A5 amplitude above the value seen with Cryo (mean difference, 2.6 mm; 95% CI, 1.1–4.1 mm; P = 0.001) (Table 5). There was strong evidence of increased FibC level after treatment compared with before treatment with Cryo (mean difference, 0.78 g/L; 95% CI, 0.34–1.2; P < 0.0005). An increase was also observed after FC treatment, but this was not markedly different to that after Cryo treatment.
Considering the whole analysed cohort, the overall trajectories of FIBTEM A5 and FibC levels are shown in Figure 4. This shows substantial and progressive increments in FIBTEM A5 and FibC. There was no suggestion of higher FIBTEM A5 or FibC levels in patients who received an intervention (FC or Cryo) compared with those who did not, although there were more FIBTEM A5 results available than FibC results.
All-cause mortality at 90 days for the whole cohort was 15.3% (n = 15) (Table 6). There were more deaths among those allocated to the FC arm (24%, n = 12) compared with those allocated to the Cryo arm (6%, n = 3). All deaths occurred within 96 hours of injury. About half of the deaths were due to head injury — six in the FC arm and one in the Cryo arm. All patients who died had a pre-hospital GCS of 3. Three patients who subsequently died had a pre-hospital cardiac arrest with return of spontaneous circulation before arrival at hospital. Two patients died of exsanguination. Two patients in the FC arm died of multiple organ failure. Twenty patients experienced a thromboembolic event (the majority of these events being venous thromboembolism) but there was no suggestion of a large difference between the two arms. Consistent with the imbalance in mortality, the FC arm had shorter median intensive care unit length of stay, median duration of mechanical ventilation and median hospital length of stay.
Early transfusion of high fixed-ratio blood products as part of a major haemorrhage protocol (MHP) in traumatic haemorrhage is beneficial for achieving haemostasis and reducing early death from exsanguination. 36
CRYOSTAT 1 reported that it is feasible to use Cryo empirically as part of a fixed ratio MHP, with a median time to administration of 60 minutes. 29
Another major difference in our trial compared with previous trials investigating fibrinogen replacement is that randomly assigned patients only received the intervention if hypofibrinogenaemia (FIBTEM A5 ≤ 10 mm) was evident and a fixed dose was not used. Of the 100 patients assigned on clinical suspicion of major haemorrhage, 65% were hypofibrinogenaemic, which is consistent with other trials where a substantial proportion of patients were not hypofibrinogenaemic at randomisation but received empiric fixed dose interventio. 31, 32
The dosing of FC and Cryo in our trial was guided by the degree of hypofibrinogenaemia. This is in contrast to previously published trials, where an empiric fixed dose of FC or Cryo was administered. In our trial, patients received a median of 3 grams of FC or a median of 8 units of Cryo, which resulted in significant increments in fibrinogen levels. The quantities of FC and Cryo required in our trial to maintain acceptable fibrinogen levels were less than those used in trials employing an empiric fixed-dose strategy. 29, 32
Blood product transfusion requirements were not different between the two arms of our trial, both at 24 hours or for the duration of hospital admission. More patients in the FC arm required surgical or interventional radiology procedures for haemorrhage control. Only two patients died of uncontrolled haemorrhage. There was no difference in the volume of crystalloid or colloid transfused between the arms, with patients receiving a median of 3.16 litres of crystalloid transfusion in the first 24 hours after injury. This is important, as there are concerns that a VHA-guided protocol using factor concentrates may result in additional non-blood product fluid resuscitation, which can be detrimental.
Even though patients in our trial were severely injured (mean ISS, 26), the mortality rate (15.3%) was less than that generally reported in trauma research publications. 4
Fibrinogen levels measured by FIBTEM A5 and FibC incremented in both arms after the intervention to levels widely accepted to be adequate for clot formation (FIBTEM A5 > 10 mm and FibC > 2 g/L). There was no suggestion in either arm that plasma fibrinogen levels after injury exceeded what would be expected subsequent to severe trauma. 29, 65
This Australian multicentre trauma transfusion trial shows that important research on severely injured multi-trauma patients can be performed in the demanding setting of trauma resuscitation. Recruitment into the trial was completed in 10 months and made possible by the research infrastructure and dedication of the project coordination team, as 62% of patients were recruited outside of standard working hours. The research infrastructure and knowledge that we gained from the FEISTY pilot trial formed the basis for a currently recruiting study on fibrinogen use in severe paediatric trauma — FEISTY Junior (NCT03508141).
Our trial has several limitations. Although it was larger than the two previous trials of FC use in trauma (FiiRST and E-FIT 1) combined, it was a small pilot feasibility trial. It was designed to evaluate the difference in time to administer fibrinogen replacement in severely injured trauma patients. It was not powered to evaluate clinical outcomes and, as such, the secondary outcome measures should be interpreted with caution. 66
The observational evidence base that supports early fibrinogen replacement in severe trauma is expanding. 19, 63, 67, 68
It is imperative that robust and clinically relevant trials are performed to investigate fibrinogen replacement strategies in severe trauma before widespread practice changes are implemented without a firm evidence base. 70, 71
The program of trauma research that we undertake is supported by grants from the Emergency Medicine Foundation (grant EMPJ357R25-2016), National Blood Authority (grant 127) and Gold Coast University Hospital (grant 150-16.6.16). This trial was supported by Werfen, Haemonetics and CSL Behring in terms of materials only. There was no industry input into trial design, data collection, data analysis or dissemination of results. Funding was managed by the coordinating site – Gold Coast University Hospital and University of Queensland.