Early administration of fibrinogen concentrate in patients with polytrauma with thromboelastometry suggestive of hypofibrinogenemia: A randomized feasibility trial
Clinics (Sao Paulo, Brazil). 2021;76:e3168
OBJECTIVE To evaluate the clinical effects of early administration of fibrinogen concentrate in patients with severe trauma and hypofibrinogenemia. METHODS We conducted an open randomized feasibility trial between December 2015 and January 2017 in patients with severe trauma admitted to the emergency department of a large trauma center. Patients presented with hypotension, tachycardia, and FIBTEM findings suggestive of hypofibrinogenemia. The intervention group received fibrinogen concentrate (50 mg/kg), and the control group did not receive early fibrinogen replacement. The primary outcome was feasibility assessed as the proportion of patients receiving the allocated treatment within 60 min after randomization. The secondary outcomes were transfusion requirements and other exploratory outcomes. Randomization was performed using sequentially numbered and sealed opaque envelopes. ClinicalTrials.gov: NCT02864875. RESULTS Thirty-two patients were randomized (16 in each group). All patients received the allocated treatment within 60 min after randomization (100%, 95% confidence interval, 86.7%-100%). The median length of intensive care unit stay was shorter in the intervention group (8 days, interquartile range [IQR] 5.75-10.0 vs. 11 days, IQR 8.5-16.0; p=0.02). There was no difference between the groups in other clinical outcomes. No adverse effects related to treatment were recorded in either group. CONCLUSION Early fibrinogen replacement with fibrinogen concentrate was feasible. Larger trials are required to properly evaluate clinical outcomes.
First-Line Administration of Fibrinogen Concentrate in the Bleeding Trauma Patient: Searching for Effective Dosages and Optimal Post-Treatment Levels Limiting Massive Transfusion-Further Results of the RETIC Study
Journal of clinical medicine. 2021;10(17)
Fibrinogen supplementation is recommended for treatment of severe trauma hemorrhage. However, required dosages and aimed for post-treatment fibrinogen levels remain a matter of discussion. Within the published RETIC study, adult patients suffering trauma-induced coagulopathy were randomly assigned to receive fibrinogen concentrate (FC) as first-line (n = 50) or crossover rescue (n = 20) therapy. Depending on bodyweight, a single dose of 3, 4, 5, or 6 g FC was administered and repeated if necessary (FibA10 < 9 mm). The dose-dependent response (changes in plasma fibrinogen and FibA10) was analyzed. Receiver operating characteristics (ROC) analysis regarding the need for massive transfusion and correlation analyses regarding fibrinogen concentrations and polymerization were performed. Median FC single doses amounted to 62.5 (57 to 66.66) mg.kg(-)(1). One FC single-dose sufficiently corrected fibrinogen and FibA10 (median fibrinogen 213 mg.dL(-1), median FibA10 11 mm) only in patients with baseline fibrinogen above 100 mg.dL(-1) and FibA10 above 5 mm, repeated dosing was required in patients with lower baseline fibrinogen/FibA10. Fibrinogen increased by 83 or 107 mg.dL(-1) and FibA10 by 4 or 4.5 mm after single or double dose of FC, respectively. ROC curve analysis revealed post-treatment fibrinogen levels under 204.5 mg.dL(-)(1) to predict the need for massive transfusion (AUC 0.652; specificity: 0.667; sensitivity: 0.688). Baseline fibrinogen/FibA10 levels should be considered for FC dosing as only sufficiently corrected post-treatment levels limit transfusion requirements.
Patients with major trauma enrolled in the RETIC study (n= 70).
Fibrinogen concentrate (FC) as first line medication (n= 50).
FC as crossover rescue medication (n= 20).
The dose-dependent response (changes in plasma fibrinogen and FibA10) was analysed. Median FC single doses amounted to 62.5 (57 to 66.66) mg.kg(-)(1). One FC single-dose sufficiently corrected fibrinogen and FibA10 (median fibrinogen 213 mg.dL(-1), median FibA10 11 mm) only in patients with baseline fibrinogen above 100 mg.dL(-1) and FibA10 above 5 mm, repeated dosing was required in patients with lower baseline fibrinogen/FibA10. Fibrinogen increased by 83 or 107 mg.dL(-1) and FibA10 by 4 or 4.5 mm after single or double dose of FC, respectively. Receiver operating characteristics curve analysis revealed post-treatment fibrinogen levels under 204.5 mg.dL(-)(1) to predict the need for massive transfusion (AUC 0.652; specificity: 0.667; sensitivity: 0.688).
Efficacy of prehospital administration of fibrinogen concentrate in trauma patients bleeding or presumed to bleed (FIinTIC): A multicentre, double-blind, placebo-controlled, randomised pilot study
European journal of anaesthesiology. 2020
BACKGROUND Trauma-induced coagulopathy (TIC) substantially contributes to mortality in bleeding trauma patients. OBJECTIVE The aim of the study was to administer fibrinogen concentrate in the prehospital setting to improve blood clot stability in trauma patients bleeding or presumed to bleed. DESIGN A prospective, randomised, placebo-controlled, double-blinded, international clinical trial. SETTING This emergency care trial was conducted in 12 Helicopter Emergency Medical Services (HEMS) and Emergency Doctors' vehicles (NEF or NAW) and four trauma centres in Austria, Germany and Czech Republic between 2011 and 2015. PATIENTS A total of 53 evaluable trauma patients aged at least 18 years with major bleeding and in need of volume therapy were included, of whom 28 received fibrinogen concentrate and 25 received placebo. INTERVENTIONS Patients were allocated to receive either fibrinogen concentrate or placebo prehospital at the scene or during transportation to the study centre. MAIN OUTCOME MEASURES Primary outcome was the assessment of clot stability as reflected by maximum clot firmness in the FIBTEM assay (FIBTEM MCF) before and after administration of the study drug. RESULTS Median FIBTEM MCF decreased in the placebo group between baseline (before administration of study treatment) and admission to the Emergency Department, from a median of 12.5 [IQR 10.5 to 14] mm to 11 [9.5 to 13] mm (P = 0.0226), but increased in the FC Group from 13 [11 to 15] mm to 15 [13.5 to 17] mm (P = 0.0062). The median between-group difference in the change in FIBTEM MCF was 5 [3 to 7] mm (P < 0.0001). Median fibrinogen plasma concentrations in the fibrinogen concentrate Group were kept above the recommended critical threshold of 2.0 g l throughout the observation period. CONCLUSION Early fibrinogen concentrate administration is feasible in the complex and time-sensitive environment of prehospital trauma care. It protects against early fibrinogen depletion, and promotes rapid blood clot initiation and clot stability. TRIAL REGISTRY NUMBERS EudraCT: 2010-022923-31 and ClinicalTrials.gov: NCT01475344.
Trauma patients with major bleeding and in need of volume therapy (n= 53).
Fibrinogen concentrate (FC), prehospital at the scene or during transportation to the study centre (n=28).
Placebo (n= 25).
Median maximum clot firmness in the FIBTEM assay decreased in patients receiving placebo between baseline (before administration of study treatment) and admission to the Emergency Department, from a median of 12.5mm to 11mm, but increased in patients receiving FC from 13mm to 15mm. The median between-group difference in the change in FIBTEM MCF was 5mm.
The effect of fibrinogen concentrate and fresh frozen plasma on the outcome of patients with acute traumatic coagulopathy: A quasi-experimental study
The American Journal of Emergency Medicine. 2018;36((11):):1947-1950
INTRODUCTION The debate on replacing coagulation factors and its effect on the final outcome of the patients with acute traumatic coagulopathy (ATC) in need of transfusion is still ongoing. Therefore, the present study is designed with the aim of comparing the outcome of patients with acute traumatic coagulopathies receiving fibrinogen and fresh frozen plasma (FFP). METHODS In this quasi-experimental randomized controlled study, patients with severe blunt trauma (ISS>16) and in need of packed cells transfusion were divided into 3 groups of receiving fibrinogen, receiving FFP, and control, and their final outcome was compared. RESULTS 90 patients with the mean age of 33.16+/-16.32years were randomly allocated to one of the 3 study groups (82.2% male). The 3 groups were similar regarding baseline characteristics. Patients receiving fibrinogen needed significantly less packed cells (p=0.044) and intravenous fluid in the initial 24h of hospitalization (p=0.022). In addition, mortality rate (p=0.029), need for admission to intensive care unit (p=0.020) and duration of hospitalization (p=0.045) were also lower in the group receiving fibrinogen. The number of sepsis cases in patients receiving fibrinogen and control group was lower than those who received FFP (p=0.001). The number of multiple organ failure cases in patients receiving fibrinogen was about one fourth of the other 2 groups (p=0.106), and a fewer number of them needed mechanical ventilation (p=0.191). No case of venous thrombosis was detected in any of the 3 groups. CONCLUSION Multiple trauma patients in need of transfusion who received fibrinogen along with packed cells had significantly better outcomes regarding mortality, sepsis, need for admission to the intensive care unit, need for receiving packed cells, need for receiving intravenous fluids in the initial 24h, and duration of hospitalization.
Early fibrinogen concentrate therapy for major haemorrhage in trauma (E-FIT 1): results from a UK multi-centre, randomised, double blind, placebo-controlled pilot trial
Critical Care (London, England). 2018;22((1)):164.
BACKGROUND There is increasing interest in the timely administration of concentrated sources of fibrinogen to patients with major traumatic bleeding. Following evaluation of early cryoprecipitate in the CRYOSTAT 1 trial, we explored the use of fibrinogen concentrate, which may have advantages of more rapid administration in acute haemorrhage. The aims of this pragmatic study were to assess the feasibility of fibrinogen concentrate administration within 45 minutes of hospital admission and to quantify efficacy in maintaining fibrinogen levels ≥ 2 g/L during active haemorrhage. METHODS We conducted a blinded, randomised, placebo-controlled trial at five UK major trauma centres with adult trauma patients with active bleeding who required activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy plus 6 g of fibrinogen concentrate or placebo. RESULTS Twenty-seven of 39 participants (69%; 95% CI, 52-83%) across both arms received the study intervention within 45 minutes of admission. There was some evidence of a difference in the proportion of participants with fibrinogen levels ≥ 2 g/L between arms (p = 0.10). Fibrinogen levels in the fibrinogen concentrate (FgC) arm rose by a mean of 0.9 g/L (SD, 0.5) compared with a reduction of 0.2 g/L (SD, 0.5) in the placebo arm and were significantly higher in the FgC arm (p < 0.0001) at 2 hours. Fibrinogen levels were not different at day 7. Transfusion use and thromboembolic events were similar between arms. All-cause mortality at 28 days was 35.5% (95% CI, 23.8-50.8%) overall, with no difference between arms. CONCLUSIONS In this trial, early delivery of fibrinogen concentrate within 45 minutes of admission was not feasible. Although evidence points to a key role for fibrinogen in the treatment of major bleeding, researchers need to recognise the challenges of timely delivery in the emergency setting. Future studies must explore barriers to rapid fibrinogen therapy, focusing on methods to reduce time to randomisation, using 'off-the-shelf' fibrinogen therapies (such as extended shelf-life cryoprecipitate held in the emergency department or fibrinogen concentrates with very rapid reconstitution times) and limiting the need for coagulation test-based transfusion triggers. TRIAL REGISTRATION ISRCTN67540073 . Registered on 5 August 2015.
The use of fibrinogen concentrate for the management of trauma-related bleeding: a systematic review and meta-analysis
Blood Transfusion.. 2017;15((4)):318-324.
Haemorrhage following injury is associated with significant morbidity and mortality. The role of fibrinogen concentrate in trauma-induced coagulopathy has been the object of intense research in the last 10 years and has been systematically analysed in this review. A systematic search of the literature identified six retrospective studies and one prospective one, involving 1,650 trauma patients. There were no randomised trials. Meta-analysis showed that fibrinogen concentrate has no effect on overall mortality (risk ratio: 1.07, 95% confidence interval: 0.83-1.38). Although the meta-analytic pooling of the current literature evidence suggests no beneficial effect of fibrinogen concentrate in the setting of severe trauma, the quality of data retrieved was poor and the final results of ongoing randomised trials will help to further elucidate the role of fibrinogen concentrate in traumatic bleeding.
Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial
British Journal of Anaesthesia. 2016;117((6)):775-782.
BACKGROUND Decreased plasma fibrinogen concentration shortly after injury is associated with higher blood transfusion needs and mortality. In North America and the UK, cryoprecipitate transfusion is the standard-of-care for fibrinogen supplementation during acute haemorrhage, which often occurs late during trauma resuscitation. Alternatively, fibrinogen concentrate (FC) can be beneficial in trauma resuscitation. However, the feasibility of its early infusion, efficacy and safety remain undetermined. The objective of this trial was to evaluate the feasibility, effect on clinical and laboratory outcomes and complications of early infusion of FC in trauma. METHODS Fifty hypotensive (systolic arterial pressure ≤100 mm Hg) adult patients requiring blood transfusion were randomly assigned to either 6 g of FC or placebo, between Oct 2014 and Nov 2015 at a tertiary trauma centre. The primary outcome, feasibility, was assessed by the proportion of patients receiving the intervention (FC or placebo) within one h of hospital arrival. Plasma fibrinogen concentration was measured, and 28-day mortality and incidence of thromboembolic events were assessed. RESULTS Overall, 96% (43/45) [95% CI 86-99%] of patients received the intervention within one h; 95% and 96% in the FC and placebo groups, respectively (P=1.00). Plasma fibrinogen concentrations remained higher in the FC group up to 12 h after admission with the largest difference at three h (2.9 mg dL - 1 vs. 1.8 mg dL - 1; P<0.01). The 28-day mortality and thromboembolic complications were similar between groups. CONCLUSIONS Early infusion of FC is feasible and increases plasma fibrinogen concentration during trauma resuscitation. Larger trials are justified.
Colloid with high fresh frozen plasma/red blood cell resuscitation does not reduce postoperative fluid needs
The Journal of Trauma and Acute Care Surgery. 2014;76((4):):1008-12.
BACKGROUND Recent data suggest that intraoperative (Phase I) colloid (human serum albumin [HSA]) and a high fresh frozen plasma (FFP)/red blood cell (RBC) resuscitation will reduce postoperative (Phase II) fluid uptake. This study compares a noncolloid (balanced electrolyte solution [BES]) plus low (<0.35) FFP/RBC resuscitation (Group A) with an HSA plus high (>0.35) FFP/RBC resuscitation. METHODS A previous randomized study of 94 patients included 48 BES patients and 46 HSA patients. A Subgroup A of 25 BES patients with low FFP/RBC was compared with a Subgroup D of 21 HSA patients with high FFP/RBC. Parameters monitored included Phase I vital signs and resuscitation needs; Phase II duration, BES needs, weight gain, and hourly urine output; and postoperative plasma volume (PV) by radioiodinated serum albumin (RISA), extracellular fluid (ECF) volume by inulin space, and interstitial volume by ECF-PV. RESULTS Admission pulse (132 for A vs. 133 for D), systolic blood pressure (SBP) (74 for A vs. 74 for D) and Phase I shock time (SBP < 80 Torr; 25 for A vs. 35 for D) were similar. Phase I RBC needs (12.5 + 1.3 for A vs. 14.9 + 1.7 for D) and BES needs (8.4 + 0.6 L for A vs. 8.4 + 0.6 L for D) were similar. During Phase II, D patients had more RBC, comparable BES, and weight gain, with lower hourly urine output compared with Group A patients. CONCLUSION HSA with high FFP/RBC does not prevent Phase II fluid uptake and causes lower urine output despite increased PV. Colloid reduces glomerular filtration, increases tubular reabsorption, and increases ECF, thus, prolonging Phase II. LEVEL OF EVIDENCE Therapeutic study, level IV.
Efficacy and safety of fibrinogen concentrate in trauma patients--a systematic review
Journal of Critical Care. 2014;29((3):):471.e11-7.
PURPOSE Uncontrolled bleeding is the main preventable cause of death in severe trauma patients. Fibrinogen is the first coagulation factor to decrease during trauma-induced coagulopathy, suggesting that pharmacological replacement might assist early hemorrhage control. Several sources of fibrinogen are available; however, fibrinogen concentrate (FC) is not routinely used in trauma settings in most countries. The aim of this review is to summarize the available literature evaluating the use of FC in the management of severe trauma. METHODS Studies reporting the administration of FC in trauma patients published between January 2000 and April 2013 were identified from MEDLINE and from the Cochrane Library. RESULTS The systematic review identified 12 articles reporting FC usage in trauma patients: 4 case reports, 7 retrospective studies, and 1 prospective observational study. Three of these were not restricted to trauma patients. CONCLUSIONS Despite methodological flaws, some of the available studies suggested that FC administration may be associated with a reduced blood product requirement. Randomized trials are warranted to determine whether FC improves outcomes in prehospital management of trauma patients or whether FC is superior to another source of fibrinogen in early hospital management of trauma patients. Copyright 2014 Elsevier Inc. All rights reserved.
Albumin resuscitation for traumatic brain injury: is intracranial hypertension the cause of increased mortality?
Journal of Neurotrauma. 2013;30((7):):512-8.
Mortality is higher in patients with traumatic brain injury (TBI) resuscitated with albumin compared with saline, but the mechanism for increased mortality is unknown. In patients from the Saline vs. Albumin Fluid Evaluation (SAFE) study with TBI who underwent intracranial pressure (ICP) monitoring, interventional data were collected from randomization to day 14 to determine changes in ICP (primary outcome) and in therapies used to treat increased ICP. Pattern mixture modelling, designed to address informative dropouts, was used to compare temporal changes between the albumin and saline groups, and 321 patients were identified, of whom 164 (51.1%) received albumin and 157 (48.9%) received saline. There was a significant linear increase in mean ICP and significantly more deaths in the albumin group compared with saline when ICP monitoring was discontinued during the first week (1.30+0.33 vs. -0.37+0.36, p=0.0006; and 34.4% vs. 17.4%; p=0.006 respectively), but not when monitoring ceased during the second week (-0.08+0.44 vs. -0.23+0.38, p=0.79; and 18.6% vs. 12.1%; p=0.36 respectively). There were statistically significant differences in the mean total daily doses of morphine (-0.42+0.07 vs. -0.66+0.0, p=0.0009), propofol (-0.45+0.11 vs. -0.76+0.11; p=0.034) and norepinephrine (-0.50+0.07 vs. -0.74+0.07) and in temperature (0.03+0.03 vs. 0.16+0.03; p=0.0014) between the albumin and saline groups when ICP monitoring ceased during the first week. The use of albumin for resuscitation in patients with severe TBI is associated with increased ICP during the first week. This is the most likely mechanism of increased mortality in these patients.