Major Trauma Clinical Trial
Official title:
Trauma Associated Bleeding: Effectiveness of an Early Coagulation Support Protocol. A Before and After Study
In severe trauma patients, uncontrolled bleeding is a major cause of death, partly caused by
trauma-induced coagulopathy (TIC).TIC represents a severe post-traumatic complication
associated with increased transfusion requirements and worsened mortality. Fibrinolysis is a
central part of the TIC process. Massive Transfusion Protocols (MTPs) were introduced as part
of damage control resuscitation, with the aim to facilitate rapid blood product release and
to increase adherence to hemostatic resuscitation, In 2013, the Italian Trauma Centers
Network (TUN) developed a new treatment algorithm providing early coagulation support (ECS)
to control coagulopathy and hemorrhage in major trauma patients with a clinically relevant
bleeding risk. The protocol includes the use of fibrinogen concentrate and RBC during initial
resuscitation, and the early use of viscoelastic techniques when available
(thromboelastometry ROTEM® or thromboelastography TEG).
The aim of this multicenter, before and after study was to assess the effects of a new ECS
protocol compared to the standard MTP in terms of blood products' consumption and clinical
outcome.
In severe trauma patients, uncontrolled bleeding is a major cause of death, partly caused by
trauma-induced coagulopathy (TIC).TIC represents a severe post-traumatic complication
associated with increased transfusion requirements and worsened mortality. Fibrinolysis is a
central part of the TIC process. Damage control resuscitation is defined as rapid hemorrhage
control through early administration of blood products prevention and immediate correction of
coagulopathy, and minimization of crystalloid fluids. Massive Transfusion Protocols (MTPs)
were introduced as part of damage control resuscitation, with the aim to facilitate rapid
blood product release and to increase adherence to hemostatic resuscitation, following a
transfusion ratio of 1:1:1 of fresh frozen plasma (FFP), platelets (PLT) and packed red blood
cells (pRBC). Their activation is triggered by clinical parameters, including patients'
trauma severity, clinical signs and laboratory data, which are included in scoring systems.
In 2013, the Italian Trauma Centers Network (TUN) developed a new treatment algorithm
providing early coagulation support (ECS) to control coagulopathy and hemorrhage in major
trauma patients with a clinically relevant bleeding risk. The protocol includes the use of
fibrinogen concentrate and RBC during initial resuscitation, and the early use of
viscoelastic techniques when available (thromboelastometry ROTEM® or thromboelastography
TEG).
The aim of this multicenter, before and after study was to assess the effects of a new ECS
protocol compared to the standard MTP in terms of blood products' consumption and clinical
outcome.
We undertook a before and after study using historical controls. We included all consecutive
adult patients with major trauma at risk of bleeding admitted to the emergency department of
two referral Trauma Centres in Rome, Italy (i.e. Fondazione Policlinico Universitario A.
Gemelli and S. Camillo Hospital). Patients treated in 2011-2012 were compared to patients
treated in 2013-2014. In the second period, the ECS protocol was concomitantly implemented as
standard of care in both trauma centers. Informed consent was waived as all the procedures
were considered the standard of care in both periods.
During the control period (pre-ECS), patients were treated according to a MTP with the
following targets: FFP/PRBC ratio ≥ 1:1.5, target platelet count > 100.000 x 109/L. According
to the ECS protocol applied in the study period, all included patients received an "initial
resuscitation" ,defined as the period between hospital admission and the first available
coagulation results (coagulation screen, fibrinogen level and/or viscoelastic monitoring and
platelet count), with a fixed initial coagulation support of tranexamic acid (TA) 1 g
intravenous bolus over 20 min followed by 1 g in continuous infusion over 8 hours and
fibrinogen concentrate (FC) 2 g bolus along with 2 to 4 units of PRBCs. Point of care (POC)
tests were systematically used to monitor coagulation and to guide subsequent interventions.
FFP was not administered in the early treatment stage. Permissive hypotension (systolic
arterial pressure 80-90 mmHg or mean arterial 50-60 mmHg) and a fluid restrictive strategy
were applied until surgical bleeding control was achieved. However, when prolonged bleeding
occurred and an increasing number of PRBCs (>4 units) and fluid volume was required (>2000
ml), plasma was transfused for hemodynamic and hemostatic resuscitation.
Data from the electronic records were matched with the blood bank registries to confirm the
number of blood units transfused within the study's time span. For patients transferred from
other hospitals, information regarding transfusions administered before admission were
collected and matched with the blood banks' data.
Patients' characteristics at admission are summarized through mean and standard deviation for
continuous variables. Median and interquartile range for scales and scores and relative
frequencies are used for discrete variables. We tested the null hypothesis of no association
between study period and patients' characteristics with the t-test, Wilcoxon test and
chi-square test for the three types of variables, respectively. We estimated the mean
difference in transfused units and length of stay between ECS and pre-ECS from unadjusted
Poisson models, using the delta methods to estimate the 95% confidence interval (CI) for the
mean difference. Findings were robust by replacing the Poisson model with a negative binomial
distribution. In addition, we defined "multiple transfused patients" as those experiencing
four or more RBC units during the first 24 hours. The cut-off of four PRBC units represented
the sample 75th percentile.
We investigated the association between clinical features and the probability of multiple
transfusion by means of univariate and multivariate logistic regression models. For the
mortality outcome, we estimated the Relative Risk (RR) and its' 95% CI of death within the
first 24 hours and within 28 days since admission for the post-ECS as compared to pre-ECS
patients from Poisson models without adjustment for other variables. Among those surviving
the first 24 hours, we replicated the analysis by considering death between the 2nd and the
28th day of hospital stay. Furthermore, we investigated whether differences in resources' use
and mortality between ECS and pre-ECS were related to major patients' demographic and
clinical features at presentation, including age (18-40, 40-65, 65+ years), severity of
traumatic brain injury (head AIS <4 vs. ≥ 4), and trauma severity (number of critical illness
criteria; presence/absence of each criterion). These stratified analyses were performed
including a study period patients' feature interaction in separated Poisson models and by
formally testing the null hypothesis of equal efficacy of the ECS protocol among categories
of patients through an F test. To further control for any residual difference in clinical
features between pre and ECS groups, we compared the resource consumption, the probability of
multiple transfusion and the mortality outcomes among propensity-score matched patients. The
propensity score included the following variables: age, sex, ISS, AIS head, worse SBP, base
excess, lactates, hemoglobin and platelets. For the statistical analyses, we used the SAS
software, 9.4 release (SAS Institute Inc., Cary, NC, US). The propensity score matching was
performed using a standard macro.
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