Over the last decade, massive transfusion protocols with fixed high plasma to red blood cell (RBC) ratios have become standard in trauma care. However, one recent randomised controlled trial did not demonstrate superiority of this strategy compared with conventional therapy for 30-day mortality.1 In contrast evidence is emerging favouring targeted, goal-directed coagulation management over protocols and fixed ratio-based strategies.2 One central and promising element of targeted and goal-directed management of trauma coagulation disorders is fibrinogen substitution. Low fibrinogen is associated with reduced clot strength and poor outcomes in trauma patients.3,4
The early identification of trauma patients with low plasma fibrinogen concentrations to enable fibrinogen substitution therapy may reduce haemorrhage and mortality, and has become standard practice in many centres. Moreover, European guidelines on management of bleeding and coagulopathy following major trauma recommend starting fibrinogen substitution when plasma fibrinogen concentrations are below 1.5 to 2 g l−1.5 However, laboratory testing is time consuming. Viscoelastic diagnostics [Thromboelastography (TEG) and thromboelastometry] are not universally available especially in resource limited or conflict settings. We hypothesised that a simple score, derived from data immediately available upon hospital admission, could be used to rapidly identify trauma patients with low plasma fibrinogen concentrations who should have fibrinogen substitution according to the European guidelines to initiate targeted procoagulant therapy as quickly as possible.
The objective of the study was to develop an easy-to-use clinical prediction score [called the Fibrinogen on Admission in Trauma (FibAT) score] to identify trauma patients with a plasma fibrinogen concentration of 1.5 g l−1 or less upon admission.
Study design and population
This study is a retrospective analysis of data derived a from a regional Trauma registry (the TraumaBase). Data for this registry are collected prospectively. This database includes trauma patients admitted to all three level 1 trauma centres in the Paris region: Beaujon University hospital, Bicêtre University hospital and Pitié-Salpêtrière University hospital. The database captures 60% of all trauma admissions from the Paris region of 12 million inhabitants, and collects extensive demographic, clinical, radiological, biological and therapeutic data as well as ICU progress and outcomes. Given the retrospective nature of the study and according to French law, the TraumaBase group obtained approval for this study, including use of data retrospectively, from the Institutional Review Board (Comité de Protection des Personnes, Paris VI, Pitié, president Pr Laurent Lacapelle, Bâtiment de la Force, 47 Boulevard de l”Hôpital, 75651 Paris Cedex 13, 28 November 2012) which is equivalent to an Ethical Committee and from the Advisory Committee for Information Processing in Health Research (Comité consultatif sur le traitement de l’information en matière de recherche dans le domaine de la santé, authorisation 11.305bis) and from the National Commission for Data Protection (Commission Nationale de l’Informatique et des Libertés, authorisation 911461).
All trauma patients triaged according to French out-of-hospital trauma algorithms6 and admitted to one of the three trauma centres above between January 2011 and November 2013 were evaluated for study inclusion. Exclusion criteria were: age less than 15 years, pregnancy, congenital hypofibrinogenaemia, transfer from a primary care hospital and prehospital blood transfusion.
Data collection and selection of variables
Potential predictors of plasma fibrinogen concentrations 1.5 g l−1 or less were selected according to investigators’ consensus and the concept of a simple, easy to calculate score from variables available within 5 min of admission. Selection was refined by reviewing mechanisms and factors that could influence fibrinogen concentrations.7
The following variables were integrated into the predictive model: age, sex, mechanism of injury (penetrating or blunt), highest out of hospital heart rate (HR), lowest out of hospital arterial SBP, out of hospital capillary haemoglobin concentration (Hemocue, Radiometer Medical ApS, Copenhagen, Denmark) and hospital admission capillary haemoglobin concentration (Hemocue, Radiometer Medical ApS), change of capillary haemoglobin concentration between out of hospital and hospital admission, admission body temperature, intraabdominal fluid assessed by sonography on admission (focussed assessment sonography in trauma), suspicion of haemothorax on an admission chest X-ray, pelvic fracture on X-ray, and blood lactate concentration on admission. Continuous variables were converted to categorical variables using clinically relevant cut-offs. Of note, capillary haemoglobin concentration measurement is standard prehospital trauma care in France. To assure standardisation between the measurements, the same method was continued upon admission to hospital.
Other data extracted from the TraumaBase included population characteristics, Injury Severity Score, Simplified Acute Physiology Score II score, Sepsis-related Organ Failure Assessment score score, mortality, coagulation test results, massively transfused patients (defined as a transfusion of four or more RBC units within 6 h or more than 10 RBC units within 24 h of admission) and blood product requirements among transfused patients (RBC units, fresh frozen plasma units, apheresis platelet units, fibrinogen concentrate).
Statistical analyses and score development
The study outcome was defined as a fibrinogen blood concentration 1.5 g l−1 or less (according to the Clauss method) on admission to a trauma centre.
The prevalence of plasma fibrinogen concentrations 1.5 g l−1 or less in our trauma population was 15.6% (n = 458). Risk factors for hypofibrinogenaemia were identified from the data of two centres that were randomly chosen to serve as the derivation cohort (centres I and II). Patients from the third centre constituted the validation cohort (centre III) for external temporal validation. The proportion of patients in the derivation and validation cohort was 72% and 28%, respectively – approximately following the two-thirds to one-third rule. The rule of 10 events per variable to qualify for logistic regression analysis was respected; 320 events were recorded into the derivation cohort, allowing 32 predictive variables for logistic regression.
To compare patients with and without hypofibrinogaenemia, all categorical variables were analysed using the χ2-square test or the Fisher's exact test, as appropriate, for association with outcome. Univariate odds ratios and 95% confidence intervals (95% CI) were also estimated. After assessment of possible colinearity between categorical variables, the logistic regression model was constructed using backward stepwise selection with hypofibrinogenaemia as the dependent variable. Independent and clinically relevant predictors were entered into the model if a significant association (P < 0.05) was identified on univariate analysis. The score was then created using the predictive factors of low plasma fibrinogen identified after multivariate analysis. It was decided to attribute one point to each predictive factor. The score was the sum of all criteria presented.
To assess external validity, the score was evaluated in the validation cohort and logistic regression model calibration was assessed using the Hosmer–Lemeshow goodness-of-fit statistic (P = 0.6). Sensitivity, specificity, positive and negative predictive values and accuracy (assessed by the proportion of correctly classified patients) were calculated at each cut-off point of the FibAT score.
Missing values never exceeded 3% for any candidate variables. Variables used in the multivariate analysis were imputed in 2% of cases using the mean of the variable. All tests were two sided and a significance threshold of 0.05 was employed for all tests. The results are expressed as median and [interquartile range], or numbers and percentages. Analyses were performed using R open source software 3.1.1 (available online at http://www.R-project.org).
Between January 2011 and December 2013, 3887 patients were admitted in the three centres and screened for inclusion. In total, 2936 patients were included in the analysis: 2124 from centres I and II, assigned to the derivation cohort and 812 from centre III, assigned to the validation cohort (Fig. 1). Patient characteristics of the derivation and validation cohorts are summarised in Table 1.
Univariate analysis conducted on data from the derivation cohort between patients with plasma fibrinogen concentrations 1.5 g l−1 or less (n = 320) and plasma fibrinogen concentrations more than 1.5 g l−1 (n = 1804), identified the following predictive variables (Table 2): age less than 33 years, out of hospital HR more than 100 beats per minute, out of hospital SBP less than 100 mmHg, out of hospital capillary haemoglobin concentration less than 12 g dl−1, decrease of capillary haemoglobin concentration between out-of-hospital and hospital admission of more than 2 g dl−1, admission body temperature less than 36°C, free intraabdominal fluid on sonography, suspicion of haemothorax on chest X-ray, pelvic fracture, open fracture and an admission blood lactate concentration of more than 2.5 mmol l−1.
A multivariate logistic regression model identified the following independent predictive factors for plasma fibrinogen concentrations 1.5 g l−1 or less on admission (Table 3): age less than 33 years, out-of-hospital HR more than 100 beats per minute, out-of-hospital SBP less than 100 mmHg, capillary haemoglobin concentration on admission less than 12 g dl−1, DHb (Out hospital – admission) >2g dl-1,temperature less than 36°C, free intraabdominal fluid on sonography and blood lactate level on admission of more than 2.5 mmol l−1. One point was given for each predictive item: these were summed to provide the FibAT score, ranging from 0 to 8 points. The area under the curve for the derivation cohort was 0.87 [95% CI (0.86 to 0.91)].
The area under the receiver operating characteristic curve was 0.82 [95% CI (0.86 to 0.91)] (Fig. 2). Determination of the FibAT score predictive performance on the validation cohort showed that the most appropriate cut-off score to identify trauma patients with plasma fibrinogen concentrations 1.5 g l−1 or less on admission was 5 points, with a specificity of 98%, a negative predictive value of 87% and an accuracy of 86% (Table 4). Using a 5-point score cut-off, the positive likelihood ratio was 23 and negative likelihood ratio was 0.55. This is a favourable result given the overall incidence of plasma fibrinogen concentrations of 1.5 g l−1 or less at just 17% in the validation cohort.
The FibAT score allows prediction of plasma fibrinogen concentrations of 1.5 g l−1 or less on admission in trauma patients. The score performed well: a FibAT score of 5 points or more indicates a high probability of a fibrinogen concentration below 1.5 g dl−1; when the FibAT score is less than 5 points, the probability of hypofibrinogenaemia is low. This study uses the current European trauma guideline recommendations as its starting point and should not be considered as evaluation of the therapeutic benefit of fibrinogen replacement.
Trauma-associated coagulopathy occurs very early following injury. Floccard et al.8 showed that 46% of trauma patients had coagulopathy at the trauma scene and that 60% had abnormal coagulation status on admission. This strongly suggests that haemostatic resuscitation should be started as soon as possible, a rationale supported by the results from the Crash-2 trial.9 Despite the lack of randomised controlled trials examining early fibrinogen therapy in trauma haemorrhage, observational data following major trauma10 and one randomised trial after aortic surgery11 both suggest a strong benefit, and only large doses of fibrinogen in the form of cryoprecipitate or fibrinogen concentrate seem to correct trauma-associated coagulopathy.12 Thus, the European guidelines on bleeding management after major trauma recommend fibrinogen substitution in the form of concentrate or cryoprecipitate in uncontrolled bleeding in trauma patients whose plasma fibrinogen concentration is less than 1.5 to 2 g l−1.5 Evidence suggests that initiation of haemostatic treatment is still often delayed, especially fibrinogen substitution.13 The aim of the FibAT score is to provide a tool to identify those patients with a fibrinogen concentration below the recommended level of 1.5 g l−1 as early as possible, to avoid the delay inherent in classical laboratory testing. In this respect the FibAT score differs from established or more recently developed prediction tools14,15 which indicate the overall probability of massive transfusion or coagulopathy and, therefore, trigger a global ‘all in’ haemostatic therapy. The FibAT score might accelerate targeted blood component therapy based on simple clinical criteria.
Early recognition of patients with low plasma fibrinogen concentrations is desirable, as substitution therapy should be initiated as soon as possible. The standard Clauss method of laboratory testing takes 40 to 45 min on average. Viscoelastic methods are faster – maximal clot firmness (TEG) or amplitude (Rotational thromboelastometry) take around 15 min and the FIBTEM test at 5 min correlates well with the fibrinogen concentration once the test has been launched.16 In comparison all variables of the FibAT score are available to the trauma team within the first 10 min of arrival. Viscoelastic methods may not be available because of the lack of personnel, software, consumables or reagents. The FibAT score allows targeted fibrinogen substitution when viscoelastic testing is not feasible such as in nonspecialised centres, in mass casualty events or in resource-limited situations such as military and humanitarian operations.
Hyprofibrinogenaemia is a key part of trauma coagulopathy which explains an overlap between the FibAT score with existing scores which were designed to predict massive transfusion.14,15,17 However, not all patients with low fibrinogen concentrations will require massive transfusion (16% of patients had fibrinogen concentrations ≤ 1.5 g l−1, but only 6% of patients required a massive transfusion). Early goal-directed coagulopathy therapy based on early fibrinogen replacement may prevent a yet to be determined proportion of massive transfusions. Plasma is an insufficient substitute for fibrinogen and concentrate or cryoprecipitate is often needed to achieve useful concentrations.12 Furthermore, both plasma and cryoprecipitate require thawing, so the anticipation of requirements before laboratory test results are available is useful. Some patients present with low fibrinogen concentrations without a full clinical picture that may trigger massive transfusion protocols. The FibAT score may facilitate the early administration of fibrinogen under the conditions of the European guidelines. This potential impact requires exploration in a new prospective controlled study that integrates the FibAT score into a comprehensive early goal-directed and targeted trauma coagulation management bundle.
Our study has a number of limitations. First, 11% of data were removed from the initial register because of incomplete or duplicated data. However, this percentage is relatively low compared with other studies.14
Second, the derivation and validation cohorts differed even for items that were part of the score. This approach has been recommended recently18,19 to allow external temporal validation to an initial derivation cohort. In the authors’ opinions, the discrepancies actually emphasise the external validity of the score, as it performs well, even in an independent and significantly different cohort.20,21
Third, the FibAT score was derived from a civilian cohort with a predominance of blunt injuries (91%). This may limit its validity in trauma populations with higher incidences of penetrating trauma. However, the validation cohort had a higher incidence of penetrating trauma (19%) than the derivation cohort (5%) and the score still performed well.
Fourth, the FibAT score was developed using a French cohort. French emergency medical services (EMS) may differ from other prehospital care systems, as a medical doctor is part of the standard EMS team. This is also the case in several other European countries such as Germany, Norway, Switzerland, and Austria. Capillary haemoglobin concentration measurement may not be part of standard prehospital trauma patient assessment as it is in France, but easy to adopt. Reduction in capillary haemoglobin concentration values from prehospital to admission is one of the strongest criteria in the FibAT score, perhaps reinforcing the role of prehospital capillary haemoglobin concentration testing in trauma patients. It is perhaps worth repeating at this point that capillary haemoglobin concentrations are as easy to determine as blood glucose concentrations, despite their lack of ubiquity across EMS.
Fifth, some factors have not been included in the model. Examples include fluid resuscitation, the use of colloids and time from injury.22 These factors can all impact upon plasma fibrinogen concentrations but are operator and system dependent.23 The study group deliberately decided to omit fluid challenge as a variable. The estimation of the amount of fluid given in the resuscitation phase is notoriously imprecise and as such a potential source of error. Low amounts of fluid given may actually not influence coagulation factors. Finally fluid strategies vary between countries and systems. Inclusion into the model may have decreased its external validity.
Sixth, we decided not to weigh any individual factors so as to keep the score easy to use. As Table 3 demonstrates, all retained variables’ derived odds ratios were relatively closely spread, and weighting would have little effect on the model. Furthermore, experience shows that most scores are infrequently used, probably because they are too complicated to calculate.
Finally the therapeutic impact of the score was not evaluated. This aspect was beyond the scope of the study and requires a separate prospective study.
In conclusion, the FibAT score is an easy-to-use bedside score that predicts plasma fibrinogen concentrations of 1.5 g l−1 or less in trauma patients upon admission. Identification of hypofibrinogenaemia is important in trauma management. This easy to use score could allow early goal-directed therapy to trauma patients. Further prospective studies are required to validate this approach and evaluate the therapeutic impact.
Acknowledgements relating to this article
Assistance with the study: We would like to thank Beny Charbit, MD, PhD, for counselling at the launch of the project. TG has participated as an instructor for a serious game (educational game) on major trauma care for LFB (Laboratoire Français du Biomédicament) without financial compensation.
The TraumaBase Group: Jacques Duranteau, MD, PhD (Service d’Anesthésie-Réanimation, Hôpital Bicêtre, Groupement Hôpitaux Universitaires Paris Sud, AP-HP, Kremlin Bicêtre, France); Olivier Langeron, MD, PhD (Sorbonne Universités, UPMC Université Paris 06, and Département d’Anesthésie Réanimation, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, AP-HP, Paris, France); Jean Mantz, MD, PhD (Université Denis Diderot - Paris VII, Département d’anesthésie-réanimation des Hôpitaux Universitaires Paris Nord Val de Seine); Bruno Riou, MD, PhD (Sorbonne Universités, UPMC Université Paris 06, UMRS INSERM 1166, IHU ICAN, and Service d’accueil des urgences, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, AP-HP, Paris, France); Bernard Vigué, MD (Service d’Anesthésie-Réanimation, Hôpital Bicêtre, Groupement Hôpitaux Universitaires Paris Sud, AP-HP, Kremlin Bicêtre, France.
Financial support: The trauma registry TraumaBase receives funding from the Regional Health Authority (Agence Régionale de Santé, ARS).
Conflicts of interest: AH had a consultancy activity for LFB (Laboratoire Français du Biomédicament) in the last 18 months. He advised LFB for the script of a serious game (educational game) that deals with trauma patient care. CP-B has received payments for industry supplied lectures by LFB.
Presentation: Preliminary results of the study have been presented at the SFAR and ESICM meeting in September and October 2014 in Paris.
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© 2018 European Society of Anaesthesiology
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