DAMAGE CONTROL POLITRAUMA

1. Rev Esp Anestesiol Reanim. 2019;66(7):394-
-
-404
www.elsevier.es/redar
Revista Española de Anestesiología
y Reanimación
SPECIAL ARTICLE
Damage Control Resuscitation in polytrauma patient夽
M.A. González Posadaa,b,∗
, A. Biarnés Suñea,b
, J.M. Naya Sieiroa
,
C.I. Salvadores de Arzuagaa
, M.J. Colomina Solerc,d
a
Servicio de Anestesiología y Reanimación, Hospital Universitario Vall d’Hebron, Barcelona, Spain
b
Universidad Autónoma de Barcelona, Barcelona, Spain
c
Servicio de Anestesiología y Reanimación, Hospital Universitario de Bellvitge, l’Hospitalet de Llobregat, Barcelona, Spain
d
Universidad Barcelona, Barcelona, Spain
Received 20 November 2018; accepted 18 March 2019
Available online 22 June 2019
KEYWORDS
Damage Control
Resuscitation;
Hyperfibrinolisis;
Haemorrhagic shock;
Tranexamic acid;
Traumatic
coagulopathy;
Polytrauma patient
Abstract Haemorrhagic shock is one of the main causes of mortality in severe polytrauma
patients. To increase the survival rates, a combined strategy of treatment known as Damage
Control has been developed.
The aims of this article are to analyse the actual concept of Damage Control Resuscitation
and its three treatment levels, describe the best transfusion strategy, and approach the acute
coagulopathy of the traumatic patient as an entity. The potential changes of this therapeutic
strategy over the coming years are also described.
© 2019 Sociedad Española de Anestesiologı́a, Reanimación y Terapéutica del Dolor. Published
by Elsevier España, S.L.U. All rights reserved.
PALABRAS CLAVE
Reanimación por
control de daños;
Hiperfibrinólisis;
Shock hemorrágico;
Ácido tranexámico;
Damage Control Resuscitation en el paciente traumático
Resumen El shock hemorrágico es una de las principales causas de muerte en los pacientes
politraumáticos graves. Para aumentar la supervivencia de estos pacientes se ha desarrollado
una estrategia combinada de tratamiento conocida como Control de Daños.
Los objetivos de este artículo son analizar el concepto actual de la Reanimación de Control
de Daños y sus tres niveles de tratamiento, describir la mejor estrategia transfusional y abordar
夽 Please cite this article as: González Posada MA, Biarnés Suñe A, Naya Sieiro JM, Salvadores de Arzuaga CI, Colomina Soler MJ. Damage
Control Resuscitation en el paciente traumático. Rev Esp Anestesiol Reanim. 2019;66:394-
-
-404.
∗ Corresponding author.
E-mail address: miagonza@vhebron.net (M.A. González Posada).
2341-1929/© 2019 Sociedad Española de Anestesiologı́a, Reanimación y Terapéutica del Dolor. Published by Elsevier España, S.L.U. All rights
reserved.

2. Damage Control Resuscitation in polytrauma patients 395
Coagulopatía
traumática;
Paciente
politraumático
la coagulopatía aguda del paciente traumático como entidad propia. Se describen también
los potenciales cambios que podrían producirse en los próximos años en esta estrategia de
tratamiento.
© 2019 Sociedad Española de Anestesiologı́a, Reanimación y Terapéutica del Dolor. Publicado
por Elsevier España, S.L.U. Todos los derechos reservados.
Introduction
The most common causes of death in multiple trauma
patients are bleeding and traumatic brain injury (TBI).
Polytrauma has attracted considerable interest in the last
decade due to its global impact as one of the leading causes
of preventable deaths.1
In Europe, traffic accidents are one
of the leading causes of polytrauma. According to the Global
Status Report on Road Safety 2018 published by the World
Health Organization (WHO), traffic accidents are responsi-
ble for 1.35 million deaths each year. They are already the
eighth leading cause of death for all age groups, the first
among young people, and will be the third cause of disability
in 2030.2
The evolution of polytrauma patients is highly dynamic,
compelling clinicians to constantly re-evaluate their
response to different treatments, both surgical and medical
performed simultaneously. The term Damage Control was
first used in the US Navy to define the techniques needed
to save a damaged ship by taking it to a safe port for
final repair. Surgical techniques known as damage control
surgery (DCS) were first described in the early years of the
20th century, and subsequently expanded.3
Damage Con-
trol Resuscitation (DCR) was developed later in the military
setting as a non-surgical protocol designed to stop bleed-
ing and correct or restore physiological status.4
DCR was
quickly adopted in the civilian setting and combined with
DCS to treat patients with severe polytrauma. The effec-
tiveness of DCR depends on the speed with which bleeding
is diagnosed and stopped. Therefore, the prompt use of this
strategy in the pre-hospital setting, known as Remote Dam-
age Control Resuscitation (RDCR), increases the chances of
survival.5
Damage Control Resuscitation
The aim of DCR is to rapidly control bleeding and pre-
vent coagulopathy by maintaining oxygen transport capacity
and tissue perfusion. To achieve this, 3 levels of treat-
ment are administered simultaneously: (1) haemodynamic
resuscitation by means of restrictive fluid therapy, permis-
sive hypotension, and massive transfusion; (2) metabolic
resuscitation, by protecting the patient against hypother-
mia, acidosis and hypocalcaemia, and (3) haemostatic
resuscitation, to prevent or reverse trauma-induced coag-
ulopathy.
Haemodynamic resuscitation
Restrictive fluid therapy
After decades of a liberal fluid therapy, evidence has shown
that the infusion of large volumes of fluids causes hypoxia,
acidosis, hypothermia, coagulopathy, dilutional hyperfib-
rinolysis, and multiorgan dysfunction.6
Current European
guidelines for the control and management of bleeding
in trauma patients recommend starting fluid therapy, ini-
tially restrictive, in hypotensive bleeding trauma patients,
and avoiding the use of Ringer’s lactate in TBI, due
to its capacity to induce oedema.7
Ringer’s acetate is
a balanced solution that has been shown to maintain
acid-
-
-base balance better than saline in scheduled surgery
and in the initial resuscitation of polytrauma patients
compared.8
Artificial colloids have been used for decades in patients
with bleeding when replacement with crystalloids is
insufficient to compensate for hypovolaemia, and blood
components are not yet available for transfusion. Despite
this, European guidelines on severe bleeding in polytrauma
patients suggest a restrictive use of colloids due to their
adverse effect of haemostasis.7
The expert panel from
the Trauma Hemostasis and Oxygenation Research Net-
work (THOR)9
group recently published a specific update
on the use of hydroxyethyl starches (HES), in which they
state that HESs provide good resuscitation volume in poly-
trauma patients, reduce crystalloid requirements, and do
not cause kidney injury or increase the need for blood
or blood products.9
Qureshi et al.,10
in a recent system-
atic review on the use of colloids and crystalloids in 59
clinical trials with more than 16,000 critical, polytrauma
and surgical patients, claim that the use of colloids does
not increase mortality compared to crystalloids. They also
describe the protective effect of colloids on renal function
in polytrauma patients. This is because the pathophysiology
of kidney injury in these patients is more closely related to
hypoperfusion due to hypovolaemia and hypotension, and
therefore differs from that of others critical patients, such
as septic patients, on which many unfavourable studies in
HESs are based.10
In the multicentre Prospective Observational Multi-
center Massive Transfusion study (PROMMTT)11
in over
1,000 patients, a multivariate analysis using the Injury
Severity Score (ISS) and Revised Trauma Score (RTS) showed
that patients who received 4 or more units of fluids (1 unit
being 1 L crystalloid or 0.5 L colloid or 1 bag of packed
red blood cells [PRBC], or 1 unit of fresh frozen plasma

3. 396 M.A. González Posada et al.
Table 1 Key points in the main studies referenced.
1 Data support the increasingly rational and restrictive use of fluids in
haemorrhagic shock by individualising their indications and targeting
their administration.
Chang et al., 201713
Feinman et al., 20146
2 Permissive hypotension is accepted for polytrauma patients with
haemorrhagic shock without associated neurotrauma. Blood pressure
should be normalised as soon as the focus of bleeding is controlled.
Other limitations are exsanguinated patients, the elderly, or patients
with cardiovascular diseases. The duration of permissive hypotension
has not been clearly determined. Target figures may change in
upcoming revisions.
Woolley et al., 201816
Spahn et al., 20197
Gaarder et al., 201514
Llau et al., 201515
Dünser et al., 201317
3 Haemodynamic coherence is the situation in which resuscitation
procedures that succeed in normalising haemodynamic variables are
also able to correct microcirculation and oxygen delivery to maintain
organ perfusion. Real-time measurement of microcirculation may
become one of the keys to optimal resuscitation in the near future.
Hutchings et al., 201820
Ince 201518
Tachon et al., 201419
4 Early transfusion with very high blood product ratios is a key factor
in DCR. Haemostatic drugs are part of the treatment of massive
bleeding.
Delay in activating the MTP and in the administration of the first
blood products delays haemostasis and increases mortality.
RETIC trial 201766
Nishida et al., 201763
Meyer et al., 201729
Watson et al., 201655
PROPPR Trial 201528
PROMMTT Study Group 201311,22,32
CRASH-2 201160
Brown et al., 201127
5 We recommend using a combined haemostatic resuscitation strategy
to treat trauma patients with major bleeding: early start of high
blood product ratio transfusion, with adjuvant haemostatic drugs,
mainly TXA, without waiting for the results of viscoelastography.
This should be followed, when results are available and/or bleeding
is under control, by a goal-directed strategy based on the results of
viscoelastic, which should form part of the MTP.
Gayet-Ageron et al., 201861
Winearls et al., 201768
Maegele et al., 201726
Schäfer et al., 201570
Ponschab et al., 201569
Johansson et al., 201424
Schöchl et al., 201425
DCR: Damage Control Resuscitation; MBP: massive bleeding protocol; MTP: massive transfusion protocol; TXA: tranexamic acid.
[FFP] or 1 unit of platelets) in the first 30 min of arrival
in the emergency room had an odds ratio for mortality
of 2.1 in the following 6 h, regardless of the type of fluid
administered. The study also showed that hospitals where
more crystalloids than blood products were used in the first
30 min had a higher 24-h mortality rate.11
Another recent
study associates the administration of more than 1,500 ml of
crystalloids in the emergency room with increased mortality
in elderly patients.12
All these data support the increasingly
rational and restrictive use of fluids in haemorrhagic shock
by individualising their indications and targeting their
administration13
(Table 1).
Permissive hypotension and haemodynamic coherence
Permissive hypotension assumes that patients will tolerate
blood pressure values that are sufficient to maintain tis-
sue perfusion and at the same time reduce bleeding. It is
important to bear in mind that this approach was initially
developed for cases of penetrating trauma in urban envi-
ronments with minimised delay in transferring the patient
to an appropriate facility.14
In the initial stage of DCR, per-
missive hypotension allows a systolic blood pressure (SBP)
of 80-
-
-90 mmHg to control bleeding. This value is later nor-
malised. This strategy is contraindicated in patients with
neurotrauma (severe head injury or spinal cord injury), in
whom mean arterial pressure (MAP) should be ≥80 mmHg,
despite increased bleeding, in order to prevent neurologi-
cal injury secondary to hypotension-
-
-hypoperfusion-induced
ischaemia.7,15
Other situations in which permissive hypoten-
sion is contraindicated or should be used with caution
are exsanguination, moribund patients, elderly patients,
or those with chronic cardiovascular diseases. Intravenous
vasopressors may need to be added to the fluids adminis-
tered in order to maintain blood pressure at this level7,15
(Table 1).
Permissive hypotension, if not contraindicated, should
be maintained for a limited time, and only until haemosta-
sis has been achieved. If prolonged resuscitation measures
are needed, permissive hypotension could become danger-
ous, since it increases oxygen debt in patients in shock.14
Some scientific societies are currently reconsidering these
blood pressure levels, and recommend increasing SAP above
100 mmHg, particularly if lengthy transfer to the hospi-
tal is expected. This implies that these levels should also
be reconsidered in the case of prolonged resuscitation.16
Permissive hypotension should not be seen as a static, pro-
tocolised measure for all polytrauma patients, but rather as
a context-dependent, dynamic and individualised procedure
that changes in accordance with the patient’s evolution and
treatment requirements (Table 1).

4. Damage Control Resuscitation in polytrauma patients 397
Table 2 Proposed definition of terms used in transfusions and severe bleeding.
‘‘Traditional’’ definition of MT ≥10 PRBCs over 24 h
‘‘Modern’’ dynamic MT ≥10 PRBCs over 6 h
≥4 PRBCs over 1 h with continuous bleeding
Replenishment >50% volume in 3 h
Major/severe bleeding ≥1 PRBC over 2 h and ≥5 PRBCs or death from haemorrhage over 4 h
Intensity of resuscitation Number of fluid units in the first 30 min
Critical transfusion threshold ≥3 PRBCs at any time within the first 24 h
PRBC: packed red blood cells; MT: massive transfusion.
Blood pressure levels do not reflect real tissue perfusion
and oxygenation, and normalisation of these parameters
is the ultimate goal of resuscitation.17
This is why the
concept of haemodynamic coherence, in which resuscita-
tion procedures that succeed in normalising haemodynamic
variables must also be able to correct microcirculation and
oxygen delivery to maintain organ perfusion, is particularly
important. Haemodynamic coherence is lost when resus-
citation achieves haemodynamic normalisation but does
not improve tissue perfusion parameters; this is subopti-
mal resuscitation that achieves worse outcomes.18,20
The
combination of physiological and metabolic parameters,
together with their changes over time, should form the basis
for decision making and assessment of resuscitation qual-
ity. Effective resuscitation involves adequate point-of-care
monitoring that measures the impact on the microcircu-
lation in real time and, therefore, the maintenance or
recovery of haemodynamic coherence. Over time, tech-
niques for monitoring microcirculation, such as functional
capillary density, dark field videomicroscopy for evaluating
sublingual mucosa, or the microvascular flow index, might
become the gold standard in resuscitation18,20
(Table 1).
Bleeding and massive transfusion
One of the difficulties in analysing transfusion strategies
in DCR is the great variety of definitions of bleeding and
massive transfusion in different studies. Currently, the most
widely accepted definitions of massive bleeding (MB) are:
blood loss exceeding circulating blood volume within a 24-
h period; blood loss of 50% of circulating blood volume
within a 3-h period; blood loss exceeding 150 ml/min; or life-
threatening blood loss that necessitates plasma and platelet
transfusion.21
The standard definition of massive transfusion
(MT), namely, loss of 10 or more PRBCs in a 24-h period, is
neither practical nor valid as a marker of severe bleeding,
and cannot be used to quickly evaluate a seriously ill patient.
There is little point in insisting that quality care in a bleeding
trauma patient must administered within the golden hour,
while the single factor that identifies a seriously ill patient
must be measured 24 h after the trauma event. MT needs to
be redefined using much shorter periods of time, with the
addition of new concepts linked to the intensity of bleed-
ing or transfusion needs during actual resuscitation. These
parameters would be more consistent with real healthcare,
and should be used to evaluate MT in future studies22.23
(Table 2).
Ideally, MB should be managed on the basis of an massive
bleeding protocol (MBP), consisting of the administration of
haemostatic drugs together with blood products following
a mass transfusion protocol (MTP). There are 2 strategies
for treating MB, which are commonly known as the Euro-
pean and American models. Both recommend the use of
viscoelastic tests (thromboelastography or thromboelastom-
etry), but the European model promotes the use of specific
clotting factor concentrates instead of the use of FFP and
cryoprecipitates, which are widely used in the American
model.13,24-
-
-26
The current trend in DCR is early transfusion
with high ratios of blood products simulating the transfu-
sion of whole blood. High ratios of 1:1:1 for PRBCs, FFP and
platelet (PL) units are influenced by the experience in mili-
tary medicine, where better survival has been reported, and
similar results have been observed for the past 10 years in
studies in civilians.27
The results of the PROMMTT study suggest that early
administration of plasma and platelets is associated with
decreased in-hospital mortality, particularly in the first few
hours of admission in patients with significant bleeding.11
More recently, a multicentre, prospective, randomised clin-
ical trial (PROPPR) analysed the effect on mortality of
transfusion of RBCs, FFP and PLs using the 2 most widely
used ratios: 1:1:1 vs 2:1:1. More than 600 trauma patients
were analysed, and although no significant difference in
mortality at 24 h or 30 days were found, more patients in
the 1:1:1 group achieved haemostasis and fewer died due
to exsanguination within 24 h (9.2% vs 14.6%), and overall
fewer blood products were required after surgery. There
were no differences in transfusion complications between
the two groups.28
The time to delivery of blood products determines out-
comes in patients with haemorrhagic shock: every minute
of delay in activating the MTP and in administering the
first transfusion increases mortality.29
In some polytrauma
patient strategies, namely RDCR, transfusions are started
before arrival at the hospital in order to waste as little time
as possible.30,31
When should a massive transfusion protocol be
activated?
Early and effective identification of patients needing MT is
essential. The decision can be based on clinical (hypoten-
sion, tachycardia, penetrating thoracoabdominal trauma or
impaired consciousness) or laboratory (clotting abnormali-
ties, base excess, low pH, low haemoglobin or the increasing
use of viscoelastic tests such as thromboelastography or
rotational thromboelastometry) parameters.

5. 398 M.A. González Posada et al.
Table 3 Examples of different scores activating a mass transfusion protocol.
ABC score Yes No
Penetrating trauma 1 0
Systolic blood pressure ≤ 90 mmHg 1 0
Heart rate ≥ 120 bpm 1 0
FAST positive 1 0
TASH variable Value Points
Haemoglobin (g/dl) <7 8
<9 6
<10 4
<11 3
<12 2
Base deficit (mmol/l) <−10 4
<−6 3
<−2 1
Systolic blood pressure (mmHg) <100 4
<120 1
Heart rate (bpm) >120 2
Free intra-abdominal fluid Yes 3
Clinically unstable pelvic fracture Yes 6
Open or dislocated femur fracture Yes 3
Male sex Yes 1
ABC score: Assessment of Blood Consumption Score, USA. Each variable can have only 2 possible values, depending on whether they are
present (Yes = 1) or absent (No = 0). A score ≥2 points activates the MTP. Very quick to perform. No laboratory variables.
TASH score: Trauma-Associated Severe Hemorrhage Score, Germany. Combines 8 variables, giving each one a value to obtain a final score
that indicates the probability of requiring MT. Its positive cut-off point is ≥16 points, indicating a 50% risk. The higher the score, the
more likely that MT will be required. For example, a TASH score of 21 points implies a 71% probability of needing MT, while 24 points
indicates a likelihood of more than 85%. It gives points to base deficit and the patient’s gender.
The most useful tools for selecting patients for MT are
scoring system (MT scores) that combine different param-
eters. These scores are useful if they are able to identify
patients with DCR criteria and trigger early activation of
the MTP. The multitude of MT score developed to date show
that none has as yet been proven to be the gold standard.32,33
The scores that are harder to calculate and perform proba-
bly give better results, but their very complexity diminishes
their usefulness and practical application when time is of
the essence. The most widely used scores include the Ameri-
can Assessment of Blood Consumption Score (ABC-score) and
the German Trauma-Associated Severe Hemorrhage Score
(TASH-score) (Table 3).
The ABC score evaluates 4 variables; if 2 are present,
the MTP is activated. The advantage of this system is that
the 4 variables are easy to remember and can be quickly
obtained, in both the hospital and pre-hospital setting. The
score has a negative predictive value (NPV) of 97%. The
drawbacks include a positive predictive value (PPV) of just
55%, meaning that a positive ABC score(≥2 points) could
lead to unnecessary activation of the MTP. The TASH-score
predicts the risk of MT and helps in MTP activation decision-
making using 8 variables developed through a multivariable
analysis of trauma patients in the Trauma Registry of the
German Trauma Society (TR-DGU).34
The TASH score has
an NPV of 94% and a PPV of 58%, according to revalidation
studies. According to these data, both scores are highly
reliable in identifying trauma patients who do not require
activation of the MTP, but show a tendency to overestimate
the need for massive transfusion. For this reason, many
societies recommend activating MTPs on the basis of these
scores combined with other factors, such as estimated
blood loss, persistence of haemodynamic instability after
initial fluid resuscitation, or the mechanism of injury.35
Other non-surgical measures for bleeding management
As a preliminary measure in both the hospital and pre-
hospital setting (RDCR), bleeding can be reduced by applying
direct pressure on the site or the correct application of
tourniquets and pelvic binders.36
Tourniquets can be dif-
ficult to apply in certain anatomical regions, such as the
neck, groin or axillar, so special tourniquets are being
developed to control bleeding proximal to the axillary and
inguinal regions, based on experience gained in combat
casualty care. More invasive measures that can be used dur-
ing DCR include interventional radiology techniques, such
as arterial embolization, which avoids the need for imme-
diate surgery.37,38
Aortic occlusion balloon catheters have
been used by interventional radiologists as an alternative
to aortic clamping or thoracotomy in polytrauma patients
and in several other scenarios, such as postpartum bleed-
ing or ruptured aortic aneurysm.39
These devices can only
be used by experienced radiologists, and the technique
is usually reserved for patients with major bleeding and
haemodynamic instability. Insertion of the catheter can be
hindered by the presence of a pelvic binder, a fairly com-

6. Damage Control Resuscitation in polytrauma patients 399
mon situation in these patients, leading some authors to
suggest that surgical control of the aorta or iliac arteries by
skilled surgeons is a more time-saving approach. Both aortic
balloon occlusion and arterial clamping will obscure distal
haemorrhage unless released prior to CT scanning.38
Metabolic resuscitation: hypothermia, acidosis and
hypocalcaemia
Many factors contribute to the onset of hypothermia,
and strategies should be established to avoid or correct
this condition, taking into account its causes: bleed-
ing, exposure to the environment, haemodynamic changes
typical of shock, fluid resuscitation, and loss of ther-
moregulation due to the interruption of normal metabolic
pathways.40
Polytrauma patients with hypothermia present
more complications, such as increased bleeding due to inhi-
bition of platelet aggregation, reduced levels of clotting and
fibrinogen synthesis factors, together with an increase in
fibrinolysis due to a decrease in levels of plasminogen acti-
vator inhibitors. As the administration of warmed fluids and
the use of external warming measures, such as blankets,
may not be sufficient to prevent hypothermia, both DCR
technique and surgical procedures should be performed in a
setting that is warm enough for this type of patient.41
Baseline lactate and base deficit (BD) levels and their
evolution are indicators of hypoperfusion or acidosis,
and have been correlated with mortality, transfusion and
coagulopathy.42
According to many authors, the evolution
of lactate levels, and not their absolute number, is the most
useful parameter for evaluating the efficacy of resuscitation
measures in polytrauma patients.43
Despite the apparent
importance of lactate, there is increasing evidence that
the behaviour and impact of this marker differ in differ-
ent types of shock, and that its predictive value is higher in
septic or cardiogenic shock than in haemorrhagic shock.44
In
fact, in the latest edition of Advanced Trauma Life Support
®
(ATLS
®
), the importance of BD is emphasised as a new fac-
tor for the classification of haemorrhagic shock, based on
evidence of its correlation with the degree of hypovolaemia
secondary to bleeding.45-
-
-47
The combination of shock and severe maintained acid-
osis is a risk factor for mortality.48
There are no specific
guidelines for the management of metabolic acidosis in
bleeding patients, and no clinical trials have clearly estab-
lished the pH cut-off point that indicates the need for
acidosis reversal in haemorrhagic shock. However, pH <7.2
seems reasonable,41
as there is evidence that lower levels
can participate in the reduction of cardiac contractility and
cardiac output, in vasodilation, hypotension and bradycar-
dia, as well as clotting factor abnormalities.49
It is advisable
to maintain calcium ions at normal levels due to their effects
on cardiac contractility, vascular tone, and their role as a
cofactor in clotting. Blood transfusions reduce calcium ion
levels due to the citrate contained in blood products. Given
the high transfusion ratios involved in current DCR strategy,
the liver’s capacity to metabolize citrate may be impaired
by factors such as shock-induced liver dysfunction, previous
liver disease, direct injury to the liver, or hypothermia.41
Calcium ions must be monitored and replaced with calcium
chloride to maintain levels at ≥1 mmol/l.15
Haemostatic resuscitation
Half of all early deaths following injury are due to bleeding,
which is still the leading cause of preventable death in the
first 24 h.50
A quarter (25%) of all severe polytrauma patients
develop trauma-induced coagulopathy (TIC).25,51
TIC is a
multifactorial failure of the coagulation system to maintain
adequate haemostasis after severe traumatic bleeding. The
presence of TIC worsens prognosis, prolongs hospital stay,
and increases transfusion requirements, the risk of organ
dysfunction, and the risk of mortality.50,51
TIC involves both
exogenous and endogenous processes (Fig. 1).
Haemodilution following fluid administration is an exoge-
nous cause of TIC, and explains the improved outcomes
achieved by limiting fluid therapy in DCR. Fatal outcome
in a patient requiring a large volume of blood products may
in part be due to the impact of transfusion-induced TIC.
Hypothermia and acidosis can exacerbate this coagulopathy.
The endogenous process behind TIC is acute traumatic
coagulopathy (ATC), caused by tissue damage and shock-
induced hypoperfusion. ATC is primarily mediated by protein
C (PC) activation, and occurs early in severely ill patients,
even before resuscitation and fluid therapy has started.
Other endogenous mechanisms, such as platelet function
defect, endotheliopathy due to glycocalyx breakdown, and
fibrinogen depletion have also been described.
After severe trauma, tissue damage and hypoperfusion
quickly trigger a process that will activate protein C (Fig. 2).
This initially facilitates thrombomodulin (TML) and endothe-
lial protein C receptor (EPCR) expression, which enhance
the activation of protein C. Circulating thrombin binds to
the PC-TML-EPCR complex and further accelerates protein
C activation (PCa). PCa inhibits factors V and VIII, which
inhibit clot formation and also reduce plasminogen activator
inhibitor-1(PAI-1) levels, leading to increased levels of tissue
plasminogen activator (tPA) and increasing fibrinolysis.
The glycocalyx, composed of proteoglycans, is part
of the endothelial barrier, and can be damaged dur-
ing haemorrhagic shock. Glycocalyx breakdown releases
glycosaminoglycans (syndecan-1, heparan sulphate or chon-
droitin sulphate), which have an anticoagulant effect. High
levels of degradation products, mainly syndecan-1, have
been associated with ATC and with increased risk of mortal-
ity in trauma patients. For this reason, some authors suggest
that strategies to protect the glycocalyx will help improve
outcomes in these patients.52-
-
-54
There is growing interest
in the possibility that FFP may contribute to glycocalyx
repair, and reports of better outcomes have been attributed
to a decrease in inflammation, oedema and vascular per-
meability, together with improved platelet function and
clot formation.55
Some patients can show a normal platelet
count, but thromboelastography (TEG) platelet mapping can
reveal the presence of platelet dysfunction. Kutcher et al.56
observed platelet aggregation alterations in 45% of poly-
trauma patients.
Fibrinolysis is the physiological process that occurs in
parallel with clot formation. It prevents clots from extend-
ing beyond the site of injury, and acts as a homeostatic
‘‘brake’’. The first problem in identifying a patient with
fibrinolysis is finding the correct measurement technique.
Viscoelastic tests, both rotational thromboelastometry

7. 400 M.A. González Posada et al.
TRAUMA:
tissue damage HAEMORRHAGE
RESUSCITATION
SHOCK
Dilution
Hypothermia
Hypothermia
ACT
TRAUMA-INDUCED COAGULOPATHY
(TIC)
Acidosis
Figure 1 Diagram of trauma-induced coagulopathy mechanisms. Trauma can cause bleeding, which is treated by administering
fluid to compensate for blood loss. This causes haemodilution and hypothermia, which alters coagulation and increases bleeding.
Haemorrhagic shock causes acidosis, hypothermia and acute trauma coagulopathy (ATC) mediated by endogenous mechanisms.
Both ATC and coagulopathy mechanisms triggered during resuscitation give rise to the general haemostasis alteration known as
trauma-induced coagulopathy (TIC).
TRAUMATIC
INJURY
CLOTTING
ANTICOAGULATION
FIBRINOLYSIS
PC
FT/VII
EPCR
TML
TML
TML
PCa
Decreased PAI-1
Increased tPA
Flla
ENDOTHELIUM
SHOCK
Flla
Inhibition V/VIII
Figure 2 Involvement of protein C in acute trauma-induced coagulopathy. After trauma, clotting is activated, giving rise to
thrombin (FIIa). Under normal conditions, FIIa activates protein C (PC). In shock, expression of endothelial thrombomodulin (TML)
is increased. When thrombin binds to the endothelial protein C receptor (EPCR) and TML, protein C activation (PCa) is greatly
accelerated. Accelerated PCa reduces levels of plasminogen activator inhibitor-1 (PAI-1), and this increases the action of tissue
plasminogen activator (tPA), accelerating the conversion of plasminogen to plasmin, which facilitates fibrinolysis and bleeding. PCa,
meanwhile, inhibits factors V and VIII, causing an anticoagulant effect.
(ROTEM) and TEG, can help us in this regard. One study
on trauma patients admitted to a specialist centre classi-
fied fibrinolysis measured by TEG into 3 levels, based on
the percentage of clot lysis at 30 min of admission: ‘‘Shut
down’’ (severe hypofibrinolysis), physiological fibrinolysis
and hyperfibrinolysis (HF).57
HF is characterised by acceler-
ated fibrin degradation that causes deficient clot formation
and haemostasis, which may manifest as diffuse bleeding
despite surgical haemostasis.58
‘‘Shut down’’, however, is
caused by low levels of fibrinolysis, and is therefore is a
prothrombotic phenomenon. Both HF and shut down are
associated with high mortality rates.59
Tranexamic acid (TXA) inhibits fibrinolysis, mainly by pre-
venting plasminogen from binding to fibrin. Current TXA
guidelines are derived from the CRASH-2 study: 1 g over
10 min, followed by an infusion of 1 g over 8 h for patients
with high energy trauma, severity criteria (SAP < 110 mmHg
and HR > 110 bpm), and suspicion of active bleeding, and
must always be started within the first 3 h of the trauma.60
In
a recent meta-analysis in over 40,000 patients, the authors
observed that TXA significantly increases survival, and every
15 min delay in administration represents a 10% decrease
in survival up to 3 h, after which there is no benefit. They
do not describe an increase in thromboembolic events with

8. Damage Control Resuscitation in polytrauma patients 401
TXA, even when it was administered late. The results of this
meta-analysis support the immediate use of TXA, which
should be included in the early pre-hospital treatment of
these patients.61
However, several groups have recently
discouraged the routine use of TXA because it increases
mortality in patients with physiological fibrinolysis, and
increases the risk of thromboembolic events in patients
with shut down fibrinolysis. This suggests that TXA is only
indicated in patients with HF, being contraindicated in
the rest.62
Various European guidelines support the pre-
hospital intravenous administration of a 1 g bolus of TXA,
withholding subsequent doses until a diagnosis of HF has
been confirmed.63
The current regimen may be modified
in the near future, and TXA may be used in a more select
group of patients after randomised studies have defined the
role of this drug in polytrauma patients, especially in the
context of the shut down effect and physiological fibrino-
lysis. Current guidelines recommend early administration
of TXA in patients with active bleeding without waiting
for viscoelastic tests,26,64
given that recent reviews con-
tinue to guarantee its efficacy and safety the earlier it is
used,61
and even describe a protective effect on glycocalyx
degradation.65
The European guidelines on the management of major
bleeding also recommend the use of FFP with PRBCs or
fibrinogen with PRBCs in patients with massive bleeding.7
Despite a higher level of scientific evidence in favour of FFP,
the use of fibrinogen concentrate as a haemostatic drug is
gaining ground, since it is the first and most severely altered
clotting factor in TIC, and is associated with a worse prog-
nosis. It is reasonable to recommend measures to increase
plasma levels of fibrinogen, and this strategy is supported by
the findings of recent studies.50,66,67
Administration of cry-
oprecipitate of fibrinogen is used for this purpose, and the
treatment is indicated by the presence of major bleeding,
ideally accompanied by signs of fibrinogen function deficit
or plasma levels of less than 1.5 g/dl. Fibrinogen concen-
trate is available in Europe, and the current recommended
average dose is 3-
-
-4 g.7
Although European guidelines recommend the use of pro-
thrombin complex concentrate (PCC) primarily for urgent
reversal of vitamin K-dependent oral anticoagulants or to
control severe bleeding in multiple trauma patients treated
with the new oral anticoagulants,7
some authors describe
using the results of viscoelastic tests to guide fibrinogen
administration, possibly in combination with PCC.24-
-
-26,66,68,69
Experts agree that the aim of DCR is to adequately restore
blood volume while avoiding or reversing TIC, but there
is no consensus on the ‘‘ideal’’ MTP, since the composi-
tion of this protocol varies in each country and hospital.70
MTPs rely on the immediate availability of blood prod-
ucts and drugs, so each hospital must adapt the protocol
to their resources. There are currently 3 types of MTPs
for severe trauma-induced bleeding: transfusion with fixed
blood product ratios, viscoelastic test-guided transfusion,
and combined or hybrid transfusion.
Viscoelastic testing can contribute to haemostatic man-
agement, and various algorithms have been developed to
interpret their results. Unfortunately, not all centres have
access to these tests, and some bleeding trauma patients
require emergency treatment consisting in the empirical
administration of haemostatic drugs while waiting for the
results of preliminary tests.25,68
European guidelines recom-
mend standard coagulation tests (TP, aPTT, platelet count
and plasma fibrinogen) and the use of viscoelastic tests.24,68
Current viscoelastic tests are unable to detect the early
stages of fibrinolysis and platelet dysfunction.
We recommend using a combined haemostatic resus-
citation strategy to treat trauma patients with major
bleeding24,68
: early start of high product-ratio transfusion
(1:1:1 or 2:1:1), with adjuvant haemostatic drugs, mainly
TXA, without waiting for the results of viscoelastography.
This should be followed, when results are available and/or
bleeding is under control, by a goal-directed strategy based
on the results of viscoelastic or laboratory tests, according
to availability, which should form part of the MTP. Fibrino-
gen must be administered in patients with major bleeding,
ideally guided by a fibrinogen concentration <1.5 g/L or vis-
coelastic evidence of a functional fibrinogen deficiency.7,26
Upcoming clinical trials, such as the ongoing Implementa-
tion of Algorithms for the Correction of Trauma-Induced
Coagulopathy (iTACTIC) trial, could show whether better
outcomes are obtained using this recent hybrid resuscitation
model (Table 1).
Conclusions
DCR is a structured, dynamic, adaptable strategy based
on haemodynamic, haemostatic and metabolic resuscitation
that can be used in severe polytrauma patients in any setting
(prehospital, emergency room, embolization room, operat-
ing room, or resuscitation-critical room). The aims of DCR
are rapid control of bleeding and prevention of coagulopa-
thy by early transfusion and minimal use of fluids. Permissive
hypotension is currently one of the key features of DCR,
but blood pressure levels should eventually be increased
until tissue oxygenation can be normalised or preserved by
means of haemodynamic coherence and protection against
glycocalyx damage. Current blood pressure goals for bleed-
ing trauma patients might be modified and/or time-limited
in the future.
Most polytrauma patients do not receive massive trans-
fusion, but those who need it benefit from a massive
transfusion protocol (MTP), and massive transfusion scores
(MT scores) should be used to identify these patients. Each
hospital treating bleeding trauma patients should develop
its own MBP, based on current scientific evidence and their
own requirements and resources.
In TIC, fibrinogen levels and clot strength are deci-
sive. Fibrinolysis is a physiological process, but HF and the
shut down effect (hypofibrinolysis) are associated with an
increase in mortality. TXA should continue to play an impor-
tant role, particularly when administered early, but doses
should probably be individualised according to the patient’s
fibrinolytic status and the stage of resuscitation.
Funding
None declared.

9. 402 M.A. González Posada et al.
Conflicts of interest
The authors have no conflict of interest related to the sci-
entific content of the article.
References
1. Jiménez Vizuete JM, Pérez Valdivieso JM, Navarro Suay R,
Gómez Garrido M, Monsalve Naharro JA, Peyró García R.
Reanimación de control de daños en el paciente adulto con
trauma grave. Rev Esp Anestesiol Reanim. 2012;59:31-
-
-42,
http://dx.doi.org/10.1016/j.redar.2011.12.001.
2. Global status report on road safety 2018. Available from:
https://www.who.int/violence injury prevention/road safety
status/2018/en/.
3. Roberts DJ, Ball CG, Feliciano DV, Moore EE, Ivatury RR,
Lucas CE, et al. History of the innovation of damage
control for management of trauma patients: 1902-
-
-2016.
Ann Surg. 2017;265:1034-
-
-44. http://www.ncbi.nlm.nih.gov/
pubmed/27232248
4. Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney
P, Mehta S, et al. Damage control resuscitation: directly
addressing the early coagulopathy of trauma. J Trauma.
2007;62:307-
-
-10.
5. Malgras B, Prunet B, Lesaffre X, Boddaert G, Travers S, Cungi
PJ, et al. Damage control: concept and implementation. J Visc
Surg. 2017;154:S19-
-
-29, http://dx.doi.org/10.1016/j.jviscsurg.
08.012.2017.
6. Feinman M, Cotton BA, Haut ER. Optimal fluid resuscita-
tion in trauma: type, timing, and total. Curr Opin Crit Care.
2014;20:366-
-
-72.
7. Spahn DR, Bouillon B, Cerny V, Duranteau J, Filipescu D, Hunt BJ,
et al. The European guideline on management of major bleed-
ing and coagulopathy following trauma: fifth edition. Crit Care.
2019;23:98.
8. Young JB, Utter GH, Schermer CR, Galante JM, Phan HH,
Yang Y, et al. Saline versus Plasma-Lyte A in initial resus-
citation of trauma patients: a randomized trial. Ann Surg.
2014;259:255-
-
-62.
9. Weiskopf RB, James MFM. Update of use of hydroxyethyl
starches in surgery and trauma. J Trauma Acute Care Surg.
2015;78 Suppl. 1:S54-
-
-9.
10. Qureshi SH, Rizvi SI, Patel NN, Murphy GJ. Meta-analysis of
colloids versus crystalloids in critically ill, trauma and surgical
patients. Br J Surg. 2016;103:14-
-
-26.
11. Holcomb JB, Fox EE, Wade CE, PROMMTT Study Group. The
PRospective Observational Multicenter Major Trauma Transfu-
sion (PROMMTT) study. J Trauma Acute Care Surg. 2013;75
Suppl. 1:S1-
-
-2.
12. Ley EJ, Clond M, Srour MK, Barnajian M, Mirocha J, Margulies
DR, et al. Emergency department crystalloid resuscitation of
1.5 L or more is associated with increased mortality in elderly
and nonelderly trauma patients. J Trauma. 2011;70:398-
-
-400.
http://www.ncbi.nlm.nih.gov/pubmed/21307740
13. Chang R, Holcomb JB. Optimal fluid therapy for traumatic hem-
orrhagic shock. Crit Care Clin. 2017;33:15-
-
-36.
14. Gaarder C, Holtan A, Naess PA. Prehospital point-of-care moni-
toring and goal-directed therapy: does it make a difference? J
Trauma Acute Care Surg. 2015;78:S60-
-
-4.
15. Llau JV, Acosta FJ, Escolar G, Fernández-Mondéjar E,
Guasch E, Marco P, et al. Documento multidisciplinar
de consenso sobre el manejo de la hemorragia masiva
(documento HEMOMAS). Med Intensiva. 2015;39:483-
-
-504,
http://dx.doi.org/10.1016/j.redar.2015.11.002.
16. Woolley T, Thompson P, Kirkman E, Reed R, Ausset S, Beckett
A, et al. Trauma Hemostasis and Oxygenation Research Network
position paper on the role of hypotensive resuscitation as part
of remote damage control resuscitation. J Trauma Acute Care
Surg. 2018;84 Suppl. 1:S3-
-
-13.
17. Dünser MW, Takala J, Brunauer A, Bakker J. Re-thinking resus-
citation: leaving blood pressure cosmetics behind and moving
forward to permissive hypotension and a tissue perfusion-based
approach. Crit Care. 2013;17:326.
18. Ince C. Hemodynamic coherence and the rationale for monitor-
ing the microcirculation. Crit Care. 2015;19 Suppl. 3:S8.
19. Tachon G, Harrois A, Tanaka S, Kato H, Huet O, Pottecher J,
et al. Microcirculatory alterations in traumatic hemorrhagic
shock. Crit Care Med. 2014;42:1433-
-
-41.
20. Hutchings SD, Naumann DN, Hopkins P, Mellis C, Riozzi P,
Sartini S, et al. Microcirculatory impairment is associated
with multiple organ dysfunction following traumatic hemor-
rhagic shock: the MICROSHOCK study. Crit Care Med. 2018;46:
e889-
-
-96.
21. Cantle PM, Cotton BA. Prediction of massive transfusion in
trauma. Crit Care Clin. 2017;33:71-
-
-84.
22. Rahbar E, Fox EE, del Junco DJ, Harvin JA, Holcomb JB, Wade
CE, et al. Early resuscitation intensity as a surrogate for bleed-
ing severity and early mortality in the PROMMTT study. J Trauma
Acute Care Surg. 2013;75 Suppl. 1:S16-
-
-23.
23. Savage SA, Zarzaur BL, Croce MA, Fabian TC. Redefining massive
transfusion when every second counts. J Trauma Acute Care
Surg. 2013;74:396-
-
-400 [discussion 400-402].
24. Johansson I, Stensballe J, Oliveri R, Wade CE, Ostrowski SR,
Holcomb JB. How I treat patients with massive hemorrhage.
Blood. 2014;124:3052-
-
-8.
25. Schöchl H, Schlimp CJ. Trauma bleeding management:
the concept of goal-directed primary care. Anesth Analg.
2014;119:1064-
-
-73.
26. Maegele M, Nardi G, Schöchl H. Hemotherapy algorithm for
the management of trauma-induced coagulopathy: the German
and European perspective. Curr Opin Anaesthesiol. 2017;30:
257-
-
-64.
27. Brown LM, Aro SO, Cohen MJ, Holcomb JB, Wade CE, Brasel KJ,
et al. A high fresh frozen plasma: packed red blood cell transfu-
sion ratio decreases mortality in all massively transfused trauma
patients regardless of admission international normalized ratio.
J Trauma. 2011;71 Suppl. 3:S358-
-
-63.
28. Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbiel-
ski JM, et al. Transfusion of plasma, platelets, and red blood
cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with
severe trauma: the PROPPR randomized clinical trial. JAMA.
2015;313:471-
-
-82.
29. Meyer DE, Vincent LE, Fox EE, O’Keeffe T, Inaba K, Bulger E,
et al. Every minute counts: time to delivery of initial massive
transfusion cooler and its impact on mortality. J Trauma Acute
Care Surg. 2017;83:19-
-
-24.
30. Spinella PC, Cap AP. Prehospital hemostatic resuscitation to
achieve zero preventable deaths after traumatic injury. Curr
Opin Hematol. 2017;24:529-
-
-35.
31. Knapp J, Pietsch U, Kreuzer O, Hossfeld B, Bernhard M, Lier
H. Prehospital blood product transfusion in mountain rescue
operations. Air Med J. 2018;37:392-
-
-9.
32. Callcut RA, Cotton BA, Muskat P, Fox EE, Wade CE, Hol-
comb JB, et al. Defining when to initiate massive transfusion:
a validation study of individual massive transfusion triggers
in PROMMTT patients. J Trauma Acute Care Surg. 2013;74:
59-
-
-68.
33. Ogura T, Lefor AK, Masuda M, Kushimoto S. Modified trau-
matic bleeding severity score: early determination of the
need for massive transfusion. Am J Emerg Med. 2016;34:
1097-
-
-101.
34. Yücel N, Lefering R, Maegele M, Vorweg M, Tjardes T, Ruchholtz
S, et al. Trauma Associated Severe Hemorrhage (TASH)-Score:
probability of mass transfusion as surrogate for life threatening

10. Damage Control Resuscitation in polytrauma patients 403
hemorrhage after multiple trauma. J Trauma. 2006;60:1228-
-
-36
[discussion 1236-1237].
35. Foster JC, Sappenfield JW, Smith RS, Kiley SP. Initiation
and termination of massive transfusion protocols: current
strategies and future prospects. Anesth Analg. 2017;125:
2045-
-
-55.
36. Van Oostendorp SE, Tan EC, Geeraedts LM Jr. Prehospital con-
trol of life-threatening truncal and junctional haemorrhage is
the ultimate challenge in optimizing trauma care: a review of
treatment options and their applicability in the civilian trauma
setting. Scand J Trauma Resusc Emerg Med. 2016;24:1-
-
-13,
http://dx.doi.org/10.1186/s13049-016-0301-9.
37. Otsuka H, Sato T, Sakurai K, Aoki H, Yamagiwa T, Iizuka S, et al.
Use of interventional radiology as initial hemorrhage control to
improve outcomes for potentially lethal multiple blunt injuries.
Injury. 2018;49:226-
-
-9.
38. Chakraverty S, Zealley I, Kessel D. Damage control radiology in
the severely injured patient: what the anaesthetist needs to
know. Br J Anaesth. 2014;113:250-
-
-7.
39. Chakraverty S, Flood K, Kessel D, McPherson S, Nicholson T, Ray
CE, et al. CIRSE guidelines: quality improvement guidelines for
endovascular treatment of traumatic hemorrhage. Cardiovasc
Intervent Radiol. 2012;35:472-
-
-82.
40. Perlman R, Callum J, Laflamme C, Tien H, Nascimento B,
Beckett A, et al. A recommended early goal-directed man-
agement guideline for the prevention of hypothermia-related
transfusion, morbidity, and mortality in severely injured trauma
patients. Crit Care. 2016;20:107.
41. Pohlman TH, Fecher AM, Arreola-Garcia C. Optimizing transfu-
sion strategies in damage control resuscitation: current insights.
J Blood Med. 2018;9:117-
-
-33.
42. Connelly CR, Schreiber MA. Endpoints in resuscitation. Curr Opin
Crit Care. 2015;21:512-
-
-9.
43. Ducrocq N, Kimmoun A, Levy B. Lactate or ScvO2 as an end-
point in resuscitation of shock states? Minerva Anestesiol.
2013;79:1049-
-
-58.
44. Cecconi M, de Backer D, Antonelli M, Beale R, Bakker J,
Hofer C, et al. Consensus on circulatory shock and hemo-
dynamic monitoring. Task Force of the European Society
of Intensive Care Medicine. Intensive Care Med. 2014;40:
1795-
-
-815.
45. Galvagno SM Jr, Nahmias JT, Young DA. Advanced Trauma
Life Support
®
Update 2019: management and applications
for adults and special populations. Anesthesiol Clin. 2019;37:
13-
-
-32.
46. Mutschler M, Nienaber U, Brockamp T, Wafaisade A, Fabian
T, Paffrath T, et al. Renaissance of base deficit for the
initial assessment of trauma patients: a base deficit-based
classification for hypovolemic shock developed on data from
16,305 patients derived from the TraumaRegister DGU
®
. Crit
Care. 2013;17:R42.
47. Mutschler M, Paffrath T, Wölfl C, Probst C, Nienaber U, Schip-
per IB, et al. The ATLS
®
classification of hypovolaemic shock:
a well established teaching tool on the edge? Injury. 2014;45:
S35-
-
-8.
48. Bakker J, Nijsten MW, Jansen TC. Clinical use of lactate mon-
itoring in critically ill patients. Ann Intensive Care. 2013;
3:12.
49. Kimmoun A, Novy E, Auchet T, Ducrocq N, Levy B. Hemody-
namic consequences of severe lactic acidosis in shock states:
from bench to bedside. Crit Care. 2015;19:175.
50. Harris T, Davenport R, Mak M, Brohi K. The evolving sci-
ence of trauma resuscitation. Emerg Med Clin North Am.
2018;36:85-
-
-106.
51. Davenport RA, Brohi K. Cause of trauma-induced coagulopathy.
Curr Opin Anaesthesiol. 2016;29:212-
-
-9.
52. Ostrowski SR, Johansson PI. Endothelial glycocalyx degrada-
tion induces endogenous heparinization in patients with severe
injury and early traumatic coagulopathy. J Trauma Acute Care
Surg. 2012;73:60-
-
-6.
53. Wei S, Gonzalez Rodriguez E, Chang R, Holcomb JB, Kao
LS, Wade CE, et al. Elevated syndecan-1 after trauma
and risk of sepsis: a secondary analysis of patients from
the Pragmatic Randomized Optimal Platelet and Plasma
Ratios (PROPPR) trial. J Am Coll Surg. 2018;227:587-
-
-95,
http://dx.doi.org/10.1016/j.jamcollsurg.2018.09.003.
54. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high
admission syndecan-1 level, a marker of endothelial glycocalyx
degradation, is associated with inflammation, protein C deple-
tion, fibrinolysis, and increased mortality in trauma patients.
Ann Surg. 2011;254:194-
-
-200.
55. Watson JJJ, Pati S, Schreiber MA. Plasma transfusion: his-
tory, current realities, and novel improvements. Shock.
2016;46:468-
-
-79.
56. Kutcher ME, Redick BJ, McCreery RC, Crane IM, Greenberg MD,
Cachola LM, et al. Characterization of platelet dysfunction after
trauma. J Trauma Acute Care Surg. 2012;73:13-
-
-9.
57. Moore HB, Moore EE, Gonzalez E, Chapman MP, Chin TL, Silliman
CC, et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibri-
nolysis shutdown: the spectrum of postinjury fibrinolysis and
relevance to antifibrinolytic therapy. J Trauma Acute Care Surg.
2014;77:811-
-
-7 [discussion 817].
58. Madurska MJ, Sachse KA, Jansen JO, Rasmussen TE, Morrison
JJ. Fibrinolysis in trauma: a review. Eur J Trauma Emerg Surg.
2018;44:35-
-
-44.
59. Moore HB, Moore EE, Liras IN, Gonzalez E, Harvin JA, Hol-
comb JB, et al. Acute fibrinolysis shutdown after injury
occurs frequently and increases mortality: a multicenter eval-
uation of 2,540 severely injured patients. J Am Coll Surg.
2016;222:347-
-
-55.
60. CRASH-2 CollaboratorsRoberts I, Shakur H, Afolabi A, Brohi K,
Coats T, et al. The importance of early treatment with tranex-
amic acid in bleeding trauma patients: an exploratory analysis
of the CRASH-2 randomised controlled trial. Lancet. 2011;377,
1096-
-
-101, 1101.e1-
-
-2.
61. Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Ageron FX,
Roberts I, et al. Effect of treatment delay on the effectiveness
and safety of antifibrinolytics in acute severe haemorrhage:
a meta-analysis of individual patient-level data from 40 138
bleeding patients. Lancet. 2018;391:125-
-
-32.
62. Taylor JR, Fox EE, Holcomb JB, Rizoli S, Inaba K, Schreiber
MA, et al. The hyperfibrinolytic phenotype is the most lethal
and resource intense presentation of fibrinolysis in massive
transfusion patients. J Trauma Acute Care Surg. 2018;84:
25-
-
-30.
63. Nishida T, Kinoshita T, Yamakawa K. Tranexamic acid and
trauma-induced coagulopathy. J Intensive Care. 2017;5:1-
-
-7,
http://dx.doi.org/10.1186/s40560-016-0201-0.
64. Gall LS, Brohi K, Davenport RA. Diagnosis and treatment of
hyperfibrinolysis in trauma (a European perspective). Semin
Thromb Hemost. 2017;43:224-
-
-34.
65. Diebel ME, Martin JV, Liberati DM, Diebel LN. The tempo-
ral response and mechanism of action of tranexamic acid in
endothelial glycocalyx degradation. J Trauma Acute Care Surg.
2018;84:75-
-
-80.
66. Innerhofer P, Fries D, Mittermayr M, Innerhofer N, von
Langen D, Hell T, et al. Reversal of trauma-induced coag-
ulopathy using first-line coagulation factor concentrates
or fresh frozen plasma (RETIC): a single-centre, parallel-
group, open-label, randomised trial. Lancet Haematol. 2017;4:
e258-
-
-71.
67. Balvers K, van Dieren S, Baksaas-Aasen K, Gaarder C, Brohi
K, Eaglestone S, et al. Combined effect of therapeutic
strategies for bleeding injury on early survival, transfusion
needs and correction of coagulopathy. Br J Surg. 2017;104:
222-
-
-9.

11. 404 M.A. González Posada et al.
68. Winearls J, Mitra B, Reade MC. Haemotherapy algorithm for the
management of trauma-induced coagulopathy: an Australian
perspective. Curr Opin Anaesthesiol. 2017;30:265-
-
-76.
69. Ponschab M, Voelckel W, Pavelka M, Schlimp CJ, Schöchl
H. Effect of coagulation factor concentrate administration
on ROTEM
®
parameters in major trauma. Scand J Trauma
Resusc Emerg Med. 2015;23:84, http://dx.doi.org/10.1186/
s13049-015-0165-4.
70. Schäfer N, Driessen A, Fröhlich M, Stürmer EK, Maegele
M, Johansson PI, et al. Diversity in clinical manage-
ment and protocols for the treatment of major bleeding
trauma patients across European level I Trauma Cen-
tres. Scand J Trauma Resusc Emerg Med. 2015;23:1-
-
-11,
http://dx.doi.org/10.1186/s13049-015-0147-6.