Schöchl et al. Critical Care 2010, 14:R55
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Open Access
RESEARCH
Goal-directed coagulation management of major
trauma patients using thromboelastometry
(ROTEM®)-guided administration of fibrinogen
concentrate and prothrombin complex
concentrate
Research
Herbert Schöchl1,2, Ulrike Nienaber3, Georg Hofer1, Wolfgang Voelckel1, Csilla Jambor4, Gisela Scharbert5,
Sibylle Kozek-Langenecker5 and Cristina Solomon*6
Abstract
Introduction: The appropriate strategy for trauma-induced coagulopathy management is under debate. We report
the treatment of major trauma using mainly coagulation factor concentrates.
Methods: This retrospective analysis included trauma patients who received ≥ 5 units of red blood cell concentrate
within 24 hours. Coagulation management was guided by thromboelastometry (ROTEM®). Fibrinogen concentrate was
given as first-line haemostatic therapy when maximum clot firmness (MCF) measured by FibTEM (fibrin-based test) was
<10 mm. Prothrombin complex concentrate (PCC) was given in case of recent coumarin intake or clotting time
measured by extrinsic activation test (EXTEM) >1.5 times normal. Lack of improvement in EXTEM MCF after fibrinogen
concentrate administration was an indication for platelet concentrate. The observed mortality was compared with the
mortality predicted by the trauma injury severity score (TRISS) and by the revised injury severity classification (RISC)
score.
Results: Of 131 patients included, 128 received fibrinogen concentrate as first-line therapy, 98 additionally received
PCC, while 3 patients with recent coumarin intake received only PCC. Twelve patients received FFP and 29 received
platelet concentrate. The observed mortality was 24.4%, lower than the TRISS mortality of 33.7% (P = 0.032) and the
RISC mortality of 28.7% (P > 0.05). After excluding 17 patients with traumatic brain injury, the difference in mortality was
14% observed versus 27.8% predicted by TRISS (P = 0.0018) and 24.3% predicted by RISC (P = 0.014).
Conclusions: ROTEM®-guided haemostatic therapy, with fibrinogen concentrate as first-line haemostatic therapy and
additional PCC, was goal-directed and fast. A favourable survival rate was observed. Prospective, randomized trials to
investigate this therapeutic alternative further appear warranted.
Introduction
Coagulopathy has been shown to be present in approximately 25 to 35% of all trauma patients on admission to
the emergency room (ER) [1,2]. This represents a serious
problem for major trauma patients and accounts for 40%
of all trauma-related deaths [3]. Coagulopathy forces a
* Correspondence: solomon.cristina@googlemail.com
6 Department of Anaesthesiology and Intensive Care, Salzburger
Landeskliniken SALK, 48 Müllner Hauptstrasse, 5020 Salzburg, Austria
Full list of author information is available at the end of the article
strategy of early and rapid haemostatic treatment to prevent exsanguination. Fresh frozen plasma (FFP) is part of
the massive transfusion protocols in most trauma centres
[3-5], although its efficacy is uncertain. Massive transfusion protocols that favour a red blood cell (RBC):FFP
ratio of 1:1 have shown conflicting results [6-14]. In addition, there are well-recognised risks associated with FFP
administration in the trauma setting, such as acute lung
injury, volume overload, and nosocomial infection
[12,15-17]. According to the Serious Hazards of Transfu-
© 2010 Schöchl et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
BioMed Central Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Schöchl et al. Critical Care 2010, 14:R55
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sion (SHOT) report, the risk of transfusion-related acute
lung injury (TRALI) following FFP transfusion is approximately 1:5000. The accumulation of 162 reports of
TRALI to SHOT over eight years, and its implication in
36 deaths and 93 cases of major morbidity, has led to the
recognition that TRALI is the most important cause of
transfusion-associated mortality and morbidity [18].
It has been shown that the amount of fibrinogen
administered to trauma patients correlates with survival
[19]. Fibrinogen concentrate [20,21] and prothrombin
complex concentrate (PCC) [22,23] have each previously
been administered to trauma and surgical patients with
success, albeit not in studies conducted exclusively in the
trauma setting. However, there have not been any studies
on the combined use of fibrinogen concentrate and PCC
for prompt haemostatic therapy in trauma patients. The
administration of coagulation factor concentrates may
facilitate early and aggressive correction of coagulopathy
by eliminating the time delay associated with crossmatching and thawing of FFP. Goal-directed haemostatic
therapy with coagulation factor concentrates may also
reduce transfusion of allogeneic blood products, which is
desirable given their negative impact on the patient outcomes.
In recent years, viscoelastic methods that assess the
speed of clotting and quality of the clot, such as thromboelastometry (ROTEM®, Tem International GmbH,
Munich, Germany), have been successfully used to guide
haemostatic therapy. Their application in the perioperative setting has been shown to decrease transfusion of
allogeneic blood products and the costs associated with
haemostatic management [24-26].
We investigated administration of fibrinogen concentrate as first-line haemostatic therapy in trauma patients
with severe bleeding; additional PCC therapy was administered as required. These treatments were guided by
thromboelastometry. Our hypothesis was that prompt,
goal-directed coagulation treatment with coagulation
factor concentrates may prove beneficial for patient outcomes. Observed mortality was compared with the mortality predicted by the trauma injury severity score
(TRISS) and by the revised injury severity classification
(RISC) score.
Materials and methods
We studied patients who received five units or more of
RBC within the first 24 hours after arrival at our trauma
centre. Since 2001, ROTEM analysis has been part of our
coagulation monitoring protocol for all trauma cases
requiring the full trauma team in the ER. We use the
ROTEM results to guide coagulation therapy, which
mainly comprises coagulation factor concentrates.
Approval from the local ethics committee was obtained
for the retrospective collection of the data. As the coagu-
Page 2 of 11
lation analyses and the haemostatic therapy were part of
the clinic's standard, the ethics committee waived the
necessity to obtained informed written consent from the
patients included in the analyses.
The coagulation management was guided by thromboelastometry performed on the ROTEM device (Tem
International GmbH, Munich, Germany). The method
measures the viscoelastic properties of the clot and provides information on the speed of coagulation initiation,
kinetics of clot growth, clot strength and breakdown [27].
The analyses are performed by pipetting 300 μl citrated
whole blood and 20 μl 0.2 M calcium chloride with specific activators into a plastic cup. Measurement of coagulation in ROTEM is performed after the vertical
immersion of a plastic pin into the blood sample. The pin
rotates slowly backwards and forwards through an angle
of 4.75°. Following generation of the first fibrin filaments
between the pin and the wall of the test cup, the rotational range of the pin is reduced. The increasing restriction of the pin's movement is transferred to a graphical
display, a plot that shows changes in the viscoelastic
properties of the clot over time. The following parameters were recorded for the ROTEM tests: clotting time
(CT (seconds); time from the start of the test until a clot
firmness of 2 mm is detected), amplitude 10 (mm), the
clot amplitude 10 minutes after the beginning of clotting)
and the maximum clot firmness (MCF (mm)). We performed extrinsically activated thromboelastometric test
(EXTEM), a test that uses rabbit brain thromboplastin as
an activator, and fibrin-based thromboelastometric test
(FibTEM), a test that assesses the fibrin-based clot using
both extrinsic activation and addition of cytochalasin D
to inhibit platelets' contribution to the formation of the
clot (Figure 1). Reference ranges for the tests' parameters
have been previously determined in a multi-centre investigation [27].
The standard protocol for ER management in our institution was followed. Blood for both ROTEM and routine
laboratory testing was drawn immediately after placement of a central venous line on admission to the ER.
Blood samples for ROTEM analysis were collected in a
standard coagulation tube containing a 0.106 M citrate
solution, resulting in a blood to citrate ratio of 9:1.
ROTEM tests were performed according to the manufacturer's recommendations, and the analyses were started
within five minutes of blood sampling. For prompt
assessment of the patient's coagulation status, preliminary test results were obtained as early as five minutes
after starting the analysis; the full results followed 10 to
20 minutes after starting the analysis. The ROTEM analyses were performed on admission to the ER and at the
end of the operation (arrival at the ICU).
In parallel, laboratory analyses were performed as follows: fibrinogen concentration on the STA-R® Analyzer
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Figure 1 The ROTEM® analyses: EXTEM® test (extrinsically activated test) and FibTEM® test (fibrin clot obtained by platelet inhibition with
cytochalasin D). The clotting time (CT (seconds)) represents the time from the start of the test until a clot firmness of 2 mm is detected; maximum
clot firmness (MCF (mm)) represents the total amplitude of the clot.
(Stago Diagnostica, Asnieres, France); prothrombin time
(PT) and activated partial thromboplastin time (aPTT)
determined on Sysmex XE-2100 (Roche Diagnostics,
Mannheim, Germany); haemoglobin, haematocrit and
platelet count determined on Sysmex SF-3000 (Sysmex
Corporation, Kobe, Japan); base excess determined on
Roche OMNI® S Blood Gas Analyzer (Roche Diagnostics,
Mannheim, Germany). Standard laboratory analyses
were performed on admission to the ER, on arrival at the
ICU and 24 hours after admission to the ER.
At the beginning of our experience with ROTEM analysis, we observed that most of the major trauma patients
showed a reduced MCF in the FibTEM test performed on
admission to the ER. Low FibTEM MCF reflects reduced
fibrinogen concentration or disturbed fibrin polymerization. To increase MCF, 2 to 4 g of fibrinogen concentrate
(Haemocomplettan® P, CSL Behring, Marburg, Germany)
were administered as first-line therapy. A FibTEM MCF
of 10 to 12 mm was chosen as the target value. Platelet
concentrate was only transfused in patients not responding sufficiently to fibrinogen concentrate (i.e. absence of
an adequate increase in MCF in the EXTEM test after the
administration of fibrinogen concentrate).
Patients with recent intake of coumarins, as well as
patients showing prolonged EXTEM CT (>1.5 times normal) received an additional 1000 to 1500 U PCC to augment thrombin generation. The following PCC products
were used from 2005 to 2009: Beriplex (CSL Behring,
Marburg, Germany), Octaplex (Octapharma, Vienna,
Austria) and Prothromplex (Baxter, Vienna, Austria).
The target haemoglobin concentration during the operative procedure was 10 g/dL. In the postoperative phase,
lower haemoglobin levels were tolerated.
Subjects' age and gender were noted, together with
coagulation results, blood pressure, heart rate, temperature, Injury Severity Score (ISS), Revised Trauma Score
and Glasgow Coma Scale (GCS) on admission. Predicted
mortality for each patient was estimated using the TRISS
methodology modified for intubated patients [28] and the
RISC score [29]. Actual mortality until discharge from the
hospital was also documented.
Statistical analysis
For all parameters, normality of the data distribution was
tested using the Kolmogorov-Smirnov test. Normally distributed results were expressed as mean ± standard deviation, and those distributed otherwise were expressed as
median (25th percentile, 75th percentile). Depending on
the underlying distribution, the Student's t-test or MannWhitney U Test was used to test for differences between
survivors and non-survivors. Mortality rates (actual vs.
TRISS or vs. RISC) were compared using the chi-squared
test. The level of significance was set at P < 0.05.
Results
From January 2005 until April 2009, 149 patients received
five or more RBC units within the first 24 hours of ICU
admission. Fifteen patients who died in the first hour
after admission, most of whom arrived under cardio-pulmonary resuscitation, were excluded from the study,
together with three patients who received no haemostatic
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therapy within the first 24 hours. Therefore, 131 patients
were included in the analysis.
Patients' characteristics are listed in Table 1. There
were 96 males and 35 females, with a mean age of 46 ± 18
years. The mean ISS was 38 ± 15. All but three patients
received immediate emergency operative care. Statistically significant differences between survivors and nonsurvivors were observed: survivors were younger, had
higher GCS scores, lower ISS and higher TRISS and RISC
scores (i.e. higher predicted survival). The mean systolic
blood pressure on admission to the ER was 88 ± 28
mmHg, with values of 100 mmHg or less in 106 patients.
The mean base excess was -6.2 ± 3.5 mmol/l, with values
of -10 mmol/l or less in 27 patients and -5 mmol/l or less
in 79 patients. Thirty-three patients had operations for
the control of abdominal, thoracic or vascular bleeding
and 74 received immediate orthopaedic fracture fixation.
Another 20 patients had combined orthopaedic and neurosurgical interventions. Three patients received no
immediate emergency procedure.
The observed mortality was 24.4%, lower than the
TRISS mortality of 33.7% (P = 0.032) and the RISC mortality of 28.7% (P > 0.05; Figure 2). After excluding 17
patients with traumatic brain injury, the difference in
mortality was 14% observed versus 27.8% predicted by
TRISS (P = 0.0018) and 24.3% predicted by RISC (P =
0.014).
The ROTEM test results on admission to the ER and on
arrival at the ICU are presented in Table 2. On admission
to the ER, the mean MCF in EXTEM was 50 mm (normal
range 53 to 72 mm). In the FibTEM test, the median MCF
was 6 mm, lower than the normal range (9 to 25 mm).
The median CT of EXTEM was within the normal range
(78 seconds, normal range 35 to 80 seconds). On admis-
sion to the ICU, thromboelastometric parameters were
comparable with the preoperative parameters.
The standard laboratory values are presented in Table
3. Mean plasma fibrinogen was 126 mg/dL on admission
to the ER and 150 mg/dL on arrival at the ICU. The mean
fibrinogen level only reached low-normal values 24 hours
after admission to the ER (228 mg/dL, normal range 200
to 450 mg/dL; Figure 3).
In patients treated with fibrinogen concentrate, a
median dose of 6 g was administered intraoperatively; the
median cumulative dose during the first 24 hours was 7 g
(Table 4). Patients who received haemostatic therapy in
the ER due to the severity of bleeding received a median
of 4 g as an initial dose. The maximum dose administered
in the ER was 14 g. Further doses of 3 to 4 g were administered during the surgery and in the ICU. Only three of
131 patients did not receive fibrinogen concentrate. A
median of six RBC units were transfused intraoperatively
and a median of 10 RBC units were transfused during the
first 24 hours. The median ratio of fibrinogen concentrate
to RBC over the first 24 hours was 0.8 g per one unit.
Despite the administration of high doses of fibrinogen
concentrate, the mean postoperative fibrinogen plasma
level was 150 mg/dL, which is below the normal range. In
patients with prolonged CT in EXTEM, a median dose of
1800 U of PCC was administered during the operation
and a median dose of 2400 U was administered during
the first 24 hours (Table 4). A total of 30 patients received
no PCC. Three patients with previous coumarin intake
received only PCC for haemostatic therapy (between
2400 and 5400 U in 24 hours) and no fibrinogen concentrate.
The timing of the administration of coagulation factor
concentrates is described in Table 5. Fifty-two percent of
Table 1: Demographic and clinical data
N
All patients
Survivors
Non-survivors
131
99 (76%)
32 (24%)
Age (years)
46 ± 18
44 ± 17
52 ± 20*
Male (n [%])
96 (73%)
72 (73%)
24 (75%)
Weight (kg)
79 ± 14
79 ± 15
78 ± 11
BMI (kg/m2)
26 ± 6
26 ± 6
27 ± 6
GCS
11 ± 4
11 ± 4
8 ± 4*
ISS
38 ± 15
36 ± 15
44 ± 15*
RTS
6.2 ± 1.5
6.5 ± 1.3
5.1 ± 1.5*
TRISS
66 ± 31
74 ± 27
46 ± 31*
RISC
71 ± 27
79 ± 22
47 ± 29*
Data are presented as mean ± standard deviation, or as absolute and relative frequency. * P < 0.05, significant difference between survivors
and non-survivors. BMI, body mass index; GCS, Glasgow Coma Scale; ISS, Injury Severity Score; n, number of patients; RISC, Revised Injury
Severity Classification Score; RTS, Revised Trauma Score; TRISS, Trauma Injury Severity Score.
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Table 2: Thromboelastometric (ROTEM) parameters
Admission at ER
Admission at ICU
EXTEM
A10 (normal range 43 to 65 mm)
40 ± 10
35 ± 9
MCF (normal range 53 to 72 mm)
50 ± 8
46 ± 8
78 (63, 113)
71 (54, 105)
A10 (normal range 7 to 23 mm)
5 (4, 7)
7 (5, 10)
MCF (normal range 9 to 25 mm)
6 (4, 8)
9 (6, 11)
CT (normal range 35 to 80 seconds)
FibTEM
Data are presented as mean ± standard deviation or as median (25th percentile, 75th percentile). A10, clot amplitude at 10 minutes after the
beginning of clot formation; CT, clotting time; ER, emergency room; EXTEM, extrinsically activated thromboelastography test; FibTEM, fibrinbased thromboelastometric test; MCF, maximum clot firmness.
patients received these products within one hour of
admission to the ER, and in most of these cases administration
was
within
30
minutes.
FFP was transfused in 12 patients, but always together
with coagulation factor concentrates. Six of the 12
patients received FFP only postoperatively, in the ICU.
Platelet concentrate was administered to 29 patients, 7 of
whom received this treatment only in the ICU. Eight
patients received recombinant activated factor VII and
another seven received tranexamic acid/aprotinin.
Discussion
In our retrospective analysis of 131 massively traumatised
and bleeding patients, ROTEM-guided haemostatic therapy with fibrinogen concentrate as first-line haemostatic
Figure 2 Comparison of the observed mortality with the mortality predicted by the trauma injury severity score (TRISS) and by
the revised injury severity classification (RISC) score. A sub-analysis that excluded patients who died of untreatable brain oedema
caused by severe brain injury was also performed.
therapy and additional PCC was goal directed and fast. A
favourable survival rate was observed.
The benefits of fibrinogen concentrate have been demonstrated in a variety of settings including trauma [1921,30-33]. In massive bleeding, fibrinogen is the first factor that reaches critically low values [34,35]. Plotkin and
colleagues showed in their study that reduced clot firmness was predictive for transfusion requirements [36].
Bolliger and colleagues investigated the minimum fibrinogen concentration above which clot formation normalises, and found that fibrinogen concentrations above 200
mg/dL are required [37]. In severe trauma, low fibrinogen
levels are reached very early because of the dilutional
effect of pre-hospital resuscitation. The mean preoperative fibrinogen plasma concentration in our patients was
126 mg/dL (shown by a FibTEM median MCF of 6 mm).
Over the 24-hour period, a cumulative median dose of 7 g
fibrinogen concentrate was applied. Despite this high
dose, the median postoperative plasma fibrinogen level
was 150 mg/dL, which is below the normal range of laboratory values.
A second argument that may support the safety of
fibrinogen supplementation is that fibrin (known as antithrombin I, and formed from fibrinogen) acts by sequestering thrombin in the incipient clot, localising the
further processes of clot formation [38,39]. Evidence of a
remarkably low thrombogenic potential of fibrinogen
concentrate has been recently presented by Dickneite and
colleagues [40]. This study included experimental data
from an animal model, and data from a 22-year pharmacovigilance program involving administration of more
than 1,000,000 g of fibrinogen (Haemocomplettan P, CSL
Behring, Marburg, Germany), equalling over 250,000
doses of 4 g. The reported incidence of thrombotic events
possibly related to fibrinogen concentrate was 3.5 per
100,000 treatment episodes.
Fibrinogen concentrate therapy may also correct or
compensate other haemostatic defects associated with
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Table 3: Standard laboratory parameters
Haemoglobin (13.5 to 17 g/dL)
Admission to the ER
Arrival at the ICU
24 hours after admission to
the ER
9.6 ± 2.8
9.6 ± 2.1
9.2 ± 1.5
Haematocrit (40 to 50%)
28 ± 8
28 ± 6
27 ± 4
Platelet count (150 to 350
*1000/μL)
166 ± 64
90 ± 49
79 ± 37
PT (11 to 13.5 seconds)
20.3 ± 8.3
22.6 ± 9.9
18.8 ± 3.2
aPTT (26 to 35 seconds)
53 ± 48
69 ± 47
49 ± 21
Fibrinogen (200 to 450 mg/dL)
126 ± 65
150 ± 50
228 ± 71
aPTT, activated partial thromboplastin time; ER, emergency room; PT, prothrombin time. Data are presented as mean ± standard deviation;
normal range is indicated in parentheses.
haemodilution, such as decreases in platelet count or
quality of fibrin polymerisation. In vitro and in vivo retrospective clinical investigations have shown that a highnormal fibrinogen level ensures satisfactory clot firmness
at low platelet counts [41,42]. In the present study,
although the median platelet count on arrival at the ER
was within the normal range, subsequent haemodilution
and consumption resulted in abnormally low values
within the following 24 hours, despite administration of
platelet concentrate. A strategy to reduce allogeneic
blood product administration may be developed based on
the possible compensatory effect of fibrinogen concentration in the presence of low platelet counts [41,42], but
Figure 3 Perioperative changes in plasma fibrinogen concentration. Measurements were performed on admission to the emergency
room (ER), on arrival at the intensive care unit (ICU), 24 hours after admission to the ER, on the third and the seventh postoperative days. The
hatched area shows the normal physiological range of plasma fibrinogen concentration. The boxes represent the interquartile range, the
lines represent the mean, and the whiskers extend to 95% confidence
interval for the mean. The circles represent outside values, larger that
the upper quartile plus 1.5 times the interquartile range, and the
squares represent far out values, larger that the upper quartile plus
three times the interquartile range.
further clinical investigations are required to support this
theory.
Volume replacement with crystalloids and colloids has
a significant deleterious effect on clot properties, because
fibrin polymerisation is impaired. This disturbance may
be corrected by fibrinogen concentrate. For example, a
study by Fenger-Eriksen and colleagues identified
acquired fibrinogen deficiency as the main determinant
of the dilutional coagulopathy induced by hydroxyethyl
starches in patients undergoing total cystectomy [43]. As
volume replacement in our trauma patients was also performed with such colloids, it is possible that fibrinogen
concentrate therapy provided additional benefit by
improving fibrin polymerisation.
PCC is recommended for emergency reversal of anticoagulation therapy [37], and its potential haemostatic
value in bleeding patients without pre-existing coagulopathy has already been shown [22,23]. In our trauma
patients, PCC was administered for the correction of the
coagulopathy associated with the prolongation of the
clotting time in the EXTEM test. PCC administration
represented the second step of haemostatic therapy, and
followed the administration of fibrinogen concentrate,
which was aimed at correcting the decreased clot firmness. Combined administration of fibrinogen concentrate
and PCC for correction of coagulopathy has already been
investigated in a porcine trauma model [30], but until
now this therapeutic approach has only been described in
a single case report [44].
FFP is advocated for haemostatic therapy in patients
with prolonged PT or aPTT [3]. However, there is a lack
of evidence demonstrating that FFP controls blood loss
[5,21]. Chowdhury and colleagues showed that 12 mL per
kg bodyweight did not sufficiently increase the concentration of the coagulation factors [45]. Moreover, there
are risks associated with FFP, such as transfusion-related
acute lung injury, transfusion-related immunosuppression and pathogen transmission. Transfusion has been
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Table 4: Haemostatic therapy and RBC transfusion
Total administered until arrival at ICU
Total administered during 24 hours after
admission to the ER
Number of patients
treated
Dose
Number of patients
treated
Dose
Fibrinogen
concentrate (g)
123
6 (4, 9)
128
7 (5, 11)
PCC (U)
83
1800 (1650, 3100)
101
2400 (1800, 3600)
FFP (U)
6
10 (7, 10)
12
10 (9.75, 11.25)
PC (U)
22
2 (1, 2)
29
2 (2, 3)
RBC (U)
125
6 (4, 10)
131
10 (6, 13)
Data are presented as median (25th percentile, 75th percentile). Total number of patients = 131. ER, emergency room; FFP, fresh frozen
plasma; PC, platelet concentrate; PCC, prothrombin complex concentrate; RBC, red blood cell concentrate.
associated with increased morbidity and mortality [1517,46-48] and these risks provide a rationale for minimising allogeneic transfusion. Furthermore, early and aggressive treatment of coagulopathy is essential in trauma
patients, and it is questionable whether FFP treatment is
compatible with this need. A study by Snyder and colleagues showed that the first FFP was given at a median of
93 minutes after arrival of the patient in the ER [49]. In
contrast, 52% of the patients in our study received the
first dose of fibrinogen concentrate within the first hour,
most of them within 30 minutes. In addition, fibrinogen
concentrate provides more effective increases in plasma
fibrinogen concentrations within a short time interval.
Within a few minutes 6 g of fibrinogen can be administered, and in our clinic coagulation factor concentrates
are stored in the ER making them readily available. In
contrast, the transfusion of FFP is time-consuming as
delivery from the blood service and thawing are required,
and there is a high volume load. Faster treatment with
coagulation factor concentrates may be one reason for
the favourable survival rate that we observed. It is also
possible that the avoidance of the side effects of FFP contributed to this finding. Unlike FFP, coagulation factor
concentrates undergo viral inactivation steps such as pasTable 5: Timing of the administration of coagulation factor
concentrates
Time of administration
Number of patients
<1 hour after arrival in ER
68
1-2 hours after arrival in ER
34
2-6 hours after arrival in ER
24
6-24 hours after arrival in ER
5
ER, emergency room.
teurisation during their manufacture, minimising the risk
of pathogen transmission.
It has been shown in the literature that 'blind' coagulation management (without point-of-care guidance)
underestimates the real demand for coagulation factors in
situations of severe bleeding [50]. Goal-directed coagulation treatment of severely bleeding patients necessitates
quick and reliable coagulation monitoring, and a targeted
therapeutic approach according to the test results [50].
Commonly used standard coagulation tests (PT and
aPTT) are time-consuming and offer poor insight into
the complex coagulopathy associated with high blood
loss, factor consumption and haemodilution [51,52]. This
makes them unsuited to guide therapeutic decisions in
emergency settings. In contrast, ROTEM and thrombelastography support an accurate and timely assessment of
not only the clotting initiation process, but also clot quality [24-26,53,54]. In animal models as well as in human
studies, thrombelastography has been shown to be a reliable monitoring tool that detects clinically relevant clotting abnormalities associated with bleeding [55,56]. In a
study that included 69 trauma patients, Kaufman and colleagues showed that only the ISS and the thrombelastography results were predictive of early transfusion
requirements [25]. Furthermore, this methodology provides immediate results and consequently allows for the
treatment to be tailored to patients' changing needs. The
number of publications reporting or encouraging the use
of ROTEM and thrombelastography for the guidance of
haemostatic therapy is increasing continuously, including
results in the trauma setting [31,44,57-61]. ROTEM tests
have even been used to establish the dosage of haemostatic products [33,62] and to support the licensing procedure of fibrinogen concentrates [63]. Yet, although
treatment algorithms based on ROTEM test results have
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been published, randomised controlled trials adopting
such algorithms are not available at the moment [58,61].
Another advantage of the application of ROTEM- or
thrombelastography-based algorithms is their potential
to reduce transfusion and associated costs and their positive impact on patient outcome. The recently published
11th Health Technology Assessment reports on the clinical and cost-effectiveness of thrombelastography and
thromboelastometry analysers compared with standard
laboratory tests. This assessment recommends the use of
these viscoelastic analyzers not only because of costeffectiveness, but also because it can reduce the need for
inappropriate transfusions and decrease blood product
requirements. Overall, the report concludes that thrombelastography and thromboelastometry appear to have a
positive impact on patient's health by reducing the number of deaths, complications and infections [64].
In the present study, observed mortality was significantly lower than the mortality predicted by TRISS
(24.4% vs 33.7%). The difference may be the result of multiple factors related to the management of trauma
patients in our clinic, and therapy with coagulation factor
concentrates could be one of these factors. The observation that the differences in mortality were even higher
after exclusion of the patients with traumatic brain injury
supports this assumption, because this group of patients
was at risk because of uncontrollable brain oedema and
not hypocoagulability. However, with the present study
design, the impact of the haemostatic therapy algorithm
on survival rate cannot be assessed separately. Furthermore, the clinical relevance of the lower observed mortality compared with the TRISS-predicted mortality must
be weighed in view of the limitations of the TRISS score
[65]. Although this score is used as a benchmark for mortality in the trauma setting, some trauma centres have
reported observed mortality rates below those predicted
by TRISS [65-67]. The greatest reduction in observed
mortality versus the mortality predicted by TRISS (22% vs
29%) was reported by Hirschmann and colleagues in a
Swiss study of 172 university hospital patients with ISS of
more than 15 [66]. The differences between the observed
and predicted mortality may be influenced by inaccuracies of the TRISS score, the level of specialisation of the
trauma care institution and by improvements in trauma
care other than coagulation management. To circumvent
these limitations, observed mortality was also compared
with the mortality predicted by the recently developed
RISC score that combines age, New Injury Severity Score,
head injury, severe pelvic injury, GCS, PTT, base excess,
cardiac arrest, and indirect signs of bleeding (shock, mass
transfusion and low haemoglobin) [29]. In development
and validation patient samples, the RISC score reached
significantly higher values for receiver operating characteristic curves compared with TRISS [29]. When applied
Page 8 of 11
to the patients included in the present study, this score
revealed mortality rates lower than TRISS-predicted
mortality, in agreement with initial reports [29]. More
importantly, RISC-predicted mortality was still higher
than the observed mortality, and the difference reached
statistical significance for the analysis that excluded
patients with traumatic brain injury. Although this finding does not prove an association of the treatment algorithm with improved survival, it supports the assumption
that trauma care incorporating ROTEM-based haemostatic therapy with coagulation factor concentrates is not
detrimental to patients.
A number of factors may have contributed to the
favourable survival rate: the promptness of the coagulation assessment (ROTEM results available in 10 to 15
minutes), the fast application of haemostatic therapy (half
of the patients received goal-directed haemostatic therapy within less than one hour after arrival in the ER) and
the high fibrinogen to RBC ratio (0.8 g: 1 unit over the
first 24 hours). Regarding the latter factor, there have
already been reports on the positive impact on survival
that a high fibrinogen to RBC ratio may have. The retrospective analysis performed by Stinger and colleagues,
which included 252 patients who received a massive
transfusion (>10 units of RBCs in 24 hours), showed a
lower incidence of death from haemorrhage in the group
of patients receiving more than 0.2 g fibrinogen per RBC
unit (mean amount of fibrinogen administered: 0.48 g
fibrinogen per RBC unit) [19]. The amount of fibrinogen
administered was calculated retrospectively as the total
content of fibrinogen in the different types of blood products administered (i.e. FFP, platelet concentrates, cryoprecipitate, fresh whole blood and RBC). In our patients,
the ratio fibrinogen to RBC was 0.8, nearly twice the ratio
reported by Stinger and colleagues, but improvement of
the fibrinogen level represented a central part of the therapeutic approach.
The main limitation of the present study is represented
by its retrospective, uncontrolled nature that does not
support an adequate estimation of the impact that therapy with coagulation factor concentrates may have had
on mortality. A retrospective analysis of data before the
introduction of thromboelastometry did not appear reasonable, because a variety of treatment protocols
changed. The study did not assess outcome parameters
apart from mortality, nor did it include comparison with
non-ROTEM-guided haemostatic therapy. The present
study was conducted over a fairly long time period (2005
to 2009), during which our experience with ROTEMbased coagulation therapy has increased and important
changes in the clinic's standard transfusion protocols
occurred. This is reflected by the fact that half of the 12
patients with FFP transfusion belong to the period 2005
to 2006. A clear reduction in intraoperative FFP transfu-
Schöchl et al. Critical Care 2010, 14:R55
http://ccforum.com/content/14/2/R55
Page 9 of 11
sion occurred from 2006 and, in the following years, FFP
has been mainly administered in isolated cases in the ICU
at the intensivist's discretion. The same pattern was followed by therapy with recombinant activated factor VII:
our records show no administration of this product in
severe trauma patients after the middle of 2007.
GS and WV contributed to the analysis of the data and to writing the manuscript. CJ contributed to acquiring the data. SKL contributed to designing the
study and writing the manuscript. CS contributed to writing the manuscript,
performed the statistical analysis and revised the manuscript.
Conclusions
ROTEM-guided haemostatic therapy with fibrinogen
concentrate as first-line haemostatic therapy and additional use of PCC was goal directed, efficacious, and
quick to administer. Thromboelastometry allowed rapid
and reliable diagnosis of the underlying coagulopathy.
Given the favourable survival rate observed, the present
data encourage prospective randomized studies based on
this treatment strategy.
Author Details
1Department of Anaesthesiology and Intensive Care, AUVA Trauma Hospital, Dr
Franz-Rehrl-Platz 5, 5010 Salzburg, Austria, 2Ludwig Boltzmann Institute for
Experimental and Clinical Traumatology, Donaueschingenstrasse 13, A-1200
Vienna, Austria, 3Institute for Research in Operative Medicine, University of
Witten/Herdecke, Cologne-Merheim Medical Center, Ostmerheimer Strasse
200, 51109 Cologne, Germany, 4Department of Anaesthesiology and Intensive
Care, Munich University Hospital, Bavariaring 19, 80336 Munich, Germany,
5Clinical Division B, Department of Anaesthesiology and General Intensive
Care, Vienna Medical University, Spitalgasse 23, 1090 Vienna, Austria and
6Department of Anaesthesiology and Intensive Care, Salzburger
Landeskliniken SALK, 48 Müllner Hauptstrasse, 5020 Salzburg, Austria
Key messages
• The present study describes goal-directed haemostatic therapy of haemorrhage in severe trauma
patients, in whom the administration of coagulation
factor concentrates was tailored to correct the haemostatic defects identified by thromboelastometric
analyses.
• The results show that coagulation factor concentrates (fibrinogen concentrate as first-line haemostatic therapy and additional PCC) can be used
successfully in trauma patients with severe bleeding.
• Thromboelastometry (ROTEM) allowed rapid and
reliable diagnosis of the underlying coagulopathy and
guided the haemostatic therapy.
• Observed mortality appeared lower than the mortality predicted by the TRISS and by the RISC score.
• This treatment strategy may reduce allogeneic blood
product transfusion, and prospective, randomized
studies appear warranted.
Abbreviations
APTT: activated partial thromboplastin time; CT: clotting time; ER: emergency
room; FFP: fresh frozen plasma; GCS: Glasgow Coma Scale; ISS: Injury Severity
Score; MCF: maximum clot firmness; PCC: prothrombin complex concentrate;
PT: prothrombin time; RBC: red blood cell; SHOT: Serious Hazards of Transfusion; TRALI: transfusion-related acute lung injury; TRISS: trauma injury severity
score.
Competing interests
This study was performed without external funding. The article-processing
charge is to be supported by the research group. Drs. Schöchl and Jambor
have received honoraria as speakers from CSL Behring (manufacturer of fibrinogen concentrate and PCC) and Tem International GmbH (manufacturer of the
ROTEM device). Dr. Solomon has received honoraria as a speaker and research
support from Essex Pharma, CSL Behring, and Tem International GmbH. Dr.
Kozek-Langenecker has received honoraria as a speaker and research support
from Astra Zeneca, Baxter (manufacturer of PCC), B.Braun, Biotest, CSL Behring,
Dynabyte, Ekomed, Fresenius Kabi, GlaxoSmithKline, Mitsubishi Pharma,
NovoNordisk, and Tem International GmbH. All other authors declare that they
have no competing interests.
Authors' contributions
HS designed the study, wrote the manuscript, contributed to acquiring the
data and revising the manuscript. UN contributed to the statistical analysis. GH,
Acknowledgements
The authors would like to thank Mr. Gerald Hochleitner for his skilled technical
assistance.
Received: 17 October 2009 Revised: 29 January 2010
Accepted: 7 April 2010 Published: 7 April 2010
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doi: 10.1186/cc8948
Cite this article as: Schöchl et al., Goal-directed coagulation management
of major trauma patients using thromboelastometry (ROTEM®)-guided
administration of fibrinogen concentrate and prothrombin complex concentrate Critical Care 2010, 14:R55
Page 11 of 11