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Effects of serum fibrinogen correction on outcome of traumatic cranial surgery: A randomized, single-blind, placebo-controlled clinical trial
Niakan A, Khalili H, Vosoughi M, Azizi E, Ghaffarpasand F
Clinical neurology and neurosurgery. 2023;229:107709
Abstract
BACKGROUND Traumatic brain injury (TBI) is strongly associated with coagulopathy that occurs in 25-35% of patients. This complication is linked to higher mortality and morbidity. Recent lines of evidance have supported administration of fibrinogen concentrate (FC) in patients with severe TBI, while its efficacy remains controversial. In this study we aim to evaluate the effectiveness of serum fibrinogen level correction from 1.5 and 2.0 g/l to more than 2.0 g/l in patients with severe TBI undergoing traumatic cranial surgery. METHOD This randomized, single-blind, placebo-controlled clinical trial included trauma patients who had abbreviated injury scale (AIS) more than 3 in head and below 3 in other organs. FC was administered intravenously to patients with severe TBI undergoing TBI to correct the fibrinogen level above 2 g/l. Patients were randomly assigned to FC and control groups. The amount of intra-operative blood loss, packed cell (PC) transfusion, formation of new intracranial hemorrhage, and hemovac drainage were compared between the two study groups. RESULTS Forty-seven of 65 participants received the study intervention within 40-112 min of admission. Intra-operative PC transfusion was higher in FC group (80%) compared to control group (55.5%) while the differance was not statistically significant (p > 0.05). Intra-operative blood loss was significantly higher in control group than FC group (P = 0.036). Chance of re-operation and new intracranial hematoma were not significantly different between two study groups. CONCLUSION Early delivery of FC, decreases intraoperative bleeding. Although based on our findings it has no other effect on other parameters, further multicenter studies are recommended to investigate the role of early FC administration in management of post traumatic coagulopathy.
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Efficacy and safety of fibrinogen administration in acute post-traumatic hypofibrinogenemia in isolated severe traumatic brain injury: A randomized clinical trial
Sabouri M, Vahidian M, Sourani A, Mahdavi SB, Tehrani DS, Shafiei E
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2022;101:204-211
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Editor's Choice
Abstract
AIM: This study was conducted to evaluate clinical outcomes after fibrinogen administration in hypofibrinogenemia following severe traumatic brain injury. BACKGROUND Post traumatic coagulopathy (PTC) is a common but devastating medical condition in patients with severe head injury. Hypofibrinogenemia is considered as an indicator for poor clinical outcomes in traumatic brain injury (TBI). METHODS In this randomized clinical trial (RCT), primarily 137 patients with severe traumatic brain injury (Glasgow coma scale score: GCS < 9) were enrolled. Thereafter, their plasma fibrinogen level was measured. The patients with primary hypofibrinogenemia (<200 mg/dL) with no concurrent coagulopathy were randomly allocated into fibrinogen-receiving (n = 50) and control (n = 54) groups. P-value < 0.05 was considered as statistically significant. RESULTS Seventy-one patients were analyzed in the final step of the study. The mean value for age in fibrinogen and control groups was 25.64 ± 10.71 and 28.91 ± 12.25 years old, respectively. Male - female patients in both groups were equally distributed. In the fibrinogen receiving group, GCS scores were significantly higher after 24, 48, and 72 h compared to the control group (p = 0.000). Hematoma expansion was better controlled in the fibrinogen receiving group (p = 0.000). Notably, the number needed to treat (NNT) for fibrinogen infusion and hematoma expansion control was 2.3. Glasgow outcome scale-extended (GOSE) was significantly better in the fibrinogen group (p = 0.25). Multiple regression tests showed intracerebral hematoma (ICH) and severe brain edema had the most detrimental effect on GOSE outcomes. The need for cranial surgery, hospital stay duration, mechanical ventilator dependency, in hospital and 90-day post discharge mortality rates were similar in both study groups. CONCLUSION In severe TBI, hypofibrinogenemia correction (>200 mg/dL) could improve GOSE, GCS score progression within 3 days after primary head injury and hematoma expansion controllability.
PICO Summary
Population
Patients with hypofibrinogenemia following severe traumatic brain injury (n= 104).
Intervention
Fibrinogen (fibrinogen group, n= 50).
Comparison
No fibrinogen (control group, n= 54).
Outcome
In the fibrinogen receiving group, Glasgow coma scale score scores were significantly higher after 24, 48, and 72 hours compared to the control group. Haematoma expansion was better controlled in the fibrinogen receiving group. The number needed to treat for fibrinogen infusion and haematoma expansion control was 2.3. Glasgow outcome scale-extended (GOSE) was significantly better in the fibrinogen group. Multiple regression tests showed intracerebral haematoma and severe brain oedema had the most detrimental effect on GOSE outcomes. The need for cranial surgery, hospital stay duration, mechanical ventilator dependency, in hospital and 90-day post discharge mortality rates were similar in both study groups.
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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
Innerhofer N, Treichl B, Rugg C, Fries D, Mittermayr M, Hell T, Oswald E, Innerhofer P, On Behalf Of The Retic Study Group
Journal of clinical medicine. 2021;10(17)
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Editor's Choice
Abstract
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.
PICO Summary
Population
Patients with major trauma enrolled in the RETIC study (n= 70).
Intervention
Fibrinogen concentrate (FC) as first line medication (n= 50).
Comparison
FC as crossover rescue medication (n= 20).
Outcome
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).
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Early administration of fibrinogen concentrate in patients with polytrauma with thromboelastometry suggestive of hypofibrinogenemia: A randomized feasibility trial
Lucena LS, Rodrigues RDR, Carmona MJC, Noronha FJD, Oliveira HP, Lima NM, Pinheiro RB, Silva WAD, Cavalcanti AB
Clinics (Sao Paulo, Brazil). 2021;76:e3168
Abstract
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.
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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
Ziegler B, Bachler M, Haberfellner H, Niederwanger C, Innerhofer P, Hell T, Kaufmann M, Maegele M, Martinowitz U, Nebl C, et al
European journal of anaesthesiology. 2020
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Editor's Choice
Abstract
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.
PICO Summary
Population
Trauma patients with major bleeding and in need of volume therapy (n= 53).
Intervention
Fibrinogen concentrate (FC), prehospital at the scene or during transportation to the study centre (n=28).
Comparison
Placebo (n= 25).
Outcome
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.
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Use of fibrinogen concentrate for trauma-related bleeding: A systematic-review and meta-analysis
Stabler, S. N., Li, S. S., Karpov, A., Vu, E. N.
The Journal of Trauma and Acute Care Surgery. 2020;89(6):1212-1224
Abstract
BACKGROUND Trauma-induced coagulopathy contributes to significant morbidity and mortality in patients who experience trauma-related bleeding. This study aimed to synthesize the evidence supporting the efficacy and safety of preemptive and goal-directed fibrinogen concentrate (FC) in the management of trauma-related hemorrhage. METHODS PubMed, Medline, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform were systematically searched. All trial designs, except individual case reports, which evaluated the preemptive or goal-directed use of FC for trauma-related bleeding/coagulopathy, in patients older than 16 years, were included in the systematic review. For the included randomized controlled trials comparing FC with control, meta-analysis was performed and a risk-of bias-assessment was completed using the Cochrane Methodology and Preferred Reporting Items Systematic Reviews and Meta-analysis guidelines. RESULTS A total of 2,743 studies were identified; 26 were included in the systematic review, and 5 randomized controlled trials (n = 238) were included in the meta-analysis. For the primary outcome of mortality, there was no statistically significant difference between the groups, with 22% and 23.4% in the FC and comparator arms, respectively (risk ratio, 1.00 [95% confidence interval, 0.39 to 2.56]; p = 0.99). In addition, there was no statistical difference between FC and control in packed red blood cell, fresh frozen plasma, or platelet transfusion requirements, and thromboembolic events. Overall, the quality of evidence was graded as low to moderate because of concerns with risk of bias, imprecision, and inconsistency. CONCLUSION Further high-quality, adequately powered studies are needed to assess the impact of FC in trauma, with a focus on administration as early as possible from the point of entry into the trauma system of care. LEVEL OF EVIDENCE Systematic review and Meta-analysis, level II.
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The effect of fibrinogen concentrate and fresh frozen plasma on the outcome of patients with acute traumatic coagulopathy: A quasi-experimental study
Akbari E, Safari S, Hatamabadi H
The American Journal of Emergency Medicine. 2018;36((11):):1947-1950
Abstract
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.
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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
Curry N, Foley C, Wong H, Mora A, Curnow E, Zarankaite A, Hodge R, Hopkins V, Deary A, Ray J, et al
Critical Care (London, England). 2018;22((1)):164.
Abstract
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.
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The use of fibrinogen concentrate for the management of trauma-related bleeding: a systematic review and meta-analysis
Mengoli C, Franchini M, Marano G, Pupella S, Vaglio S, MariettaM, Liumbruno GM
Blood Transfusion.. 2017;15((4)):318-324.
Abstract
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.
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Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial
Nascimento B, Callum J, Tien H, Peng H, Rizoli S, Karanicolas P, Alam A, Xiong W, Selby R, Garzon AM, et al
British Journal of Anaesthesia. 2016;117((6)):775-782.
Abstract
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.
