Eur J Trauma Emerg Surg

DOI 10.1007/s00068-014-0416-5

REVIEW ARTICLE

Modern resuscitation of hemorrhagic shock:

what is on the horizon?
D. T. Martin M. A. Schreiber

Received: 15 January 2014 / Accepted: 23 May 2014

Springer-Verlag Berlin Heidelberg 2014

Abstract
Purpose Mortality rates among the severely injured remain
high. The successful treatment of hemorrhagic shock relies on
expeditious control of bleeding through surgical ligation,
packing, or endovascular techniques. An important secondary
concern in hemorrhaging patients is how to respond to the lost
blood volume. A single method that is able to adequately
address all needs of the exsanguinating patient has not yet
been agreed upon, despite a large growth of knowledge
regarding the causative factors of traumatic shock.
Methods A review of relevent literature was performed.
Conclusions Many different trials are currently underway
to discriminate ways to improve outcomes in the severely
injured and bleeding patient. This paper will review: (1)
recent advances in our understanding of the effects hemorrhagic shock has on the coagulation cascade and vascular
endothelium, (2) recent research findings that have changed
resuscitation, and (3) resuscitation strategies that are not
widely used but under active investigation.
Keywords Trauma
Resuscitation
Hemorrhagic shock

Glycocalyx
Trauma-induced coagulopathy
FFP

D. T. Martin (&)
M. A. Schreiber

Division of Trauma, Critical Care, and Acute Care Surgery,
Department of Surgery, Oregon Health and Science University,
3181 SW Sam Jackson Park Road, Mail Code L-611, Portland,
OR 97239, USA
e-mail: martida@ohsu.edu
M. A. Schreiber
e-mail: schreibm@ohsu.edu
D. T. Martin
M. A. Schreiber
Division of Trauma, Critical Care, and Acute Care Surgery,
Oregon Health and Science University, 3181 SW Sam Jackson
Park Road, Mail Code L-611, Portland, OR 97239, USA

Introduction
Trauma remains a leading cause of death, with roughly
one-half of traumatic deaths occurring due to hemorrhage
[1, 2]. The successful treatment of hemorrhagic shock
relies on expeditious control of bleeding through surgical
ligation, packing, or endovascular techniques. An important secondary concern to the hemorrhaging patient is how
to respond to the lost blood volume. The physiologic and
metabolic derangements associated with hemorrhagic
shock are significant. Hypoperfusion and hypoxia present
an immediate threat to life, followed in quick succession by
acidosis, coagulopathy, hypothermia, as well as progressive endothelial damage and immune activation. Multiple
levels of dysfunction coexist, from loss of global vascular
tone down to DNA transcription patterns of individual
cells, making appropriate prioritization of the patients
needs a complex process.
What fluid should be given, at what rate, and to what
end point are all questions that have been extensively
studied over the past 100 years. This paper will review: (1)
recent advances in our understanding of the effects hemorrhagic shock has on the coagulation cascade and vascular
endothelium, (2) recent research findings that have changed
resuscitation, and (3) resuscitation strategies that are not
widely used but under active investigation.

Advances in knowledge
The specific cellular mechanisms behind the bodys
response to trauma and shock are being elucidated. Capillary leak and edema formation may be explained through
degradation of the endothelial glycocalyx border, and a
source of trauma-induced coagulopathy can be traced back

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D. T. Martin, M. A. Schreiber

Fig. 1 Electron microscopy revealing the glycocalyx border of an

isolated guinea pig heart. a The intact glycocalyx. b Denuded
glycocalyx following 20 min of ischemia. c Preservation of glycocalyx through pretreatment with antithrombin III followed by
ischemia. Re-published with permission of the European Society of
Cardiology. Chappell D et al. Cardiovasc Res 2009; 83:388396

to increased activation of protein C. A better understanding

of these processes will help guide treatment strategies.
Glycocalyx: the endothelial border
The glycocalyx (Fig. 1a) is a negatively charged, complex
meshwork of glycoproteins that covers the surface of
vascular endothelial cells. Varying in thickness from 0.2 to
1.0 lm and taking up 1520 % of the capillary lumen, it is

123

composed of long strands of glycoproteins and proteoglycans (such as syndecan-1) attached to the endothelial cell
membrane [35]. Connected to these backbone proteins are
numerous associated glycosaminoglycan side-chains over
50 % of which consist of heparin sulfate. A dynamic
equilibrium exists between the membrane bound skeleton
of the glycocalyx and soluble plasma components, where
proteins such as albumin and antithrombin III shift in and
out of solution. As a whole, the glycoprotein skeleton and
its soluble components generate a physiologic barrier
between the endothelial cell and the vascular lumen.
Within this barrier is approximately one liter of plasma
removed from general circulation.
Resuscitation and fluid management over the past century have been based on the original Starling compartment
modelwith an extracellular space divided into the vascular and extravascular compartments with a porous
endothelial barrier between. Fluid in this model shifted in
and out of the vascular space based on a balancing of
hydrostatic and oncotic pressures. This model resulted in
fluid resuscitation strategies designed to maintain intravascular volume through the use of oncotic agents such as
albumin or synthetic colloids. However, improved experimental methods in cardiovascular physiology found that
this model was unable to explain more recent observations
of fluid dynamics in the capillary [6].
To rectify the differences between the Starling Equation
and the new observations in fluid dynamics, two independent labs proposed what is known as the Michel-Weinbaum
model to incorporate the glycocalyx into the equation [7,
8]. Instead of the oncotic pressure of the blood as a whole,
it is the oncotic pressure found locally within the glycocalyx which controls fluid permeability within each individual capillary [9, 10]. Disruption of the glycocalyx layer
will upset this equilibrium, promoting fluid leak into the
interstitium and edema accumulation.
Beyond fluid regulation, the intact glycocalyx has many
roles regulating the endothelial environment. Its ability to
bind a heterogeneous mixture of enzymes enables it to
protect the endothelium from oxidative stress (through
sequestration of Super Oxide Dismutase) and thrombosis
(via such enzymes as thrombomodulin and antithrombin
III) [4]. Its physical structure prevents red cells and
platelets from contacting the endothelial cell membrane,
and it interacts with rolling leukocytes preventing adhesion
to endothelial cells [11]. These regulatory functions are lost
when the glycocalyx is shed from the endothelial cell due
to ischemic injury, enzymatic action or fluid shear forces.
Damage to vascular endothelium occurs along a spectrum varying from disruption of the entire endothelial cell
layer, complete loss of the glycocalyx border, or shedding
of the soluble plasma components of the glycocalyx.
Destruction of the glycocalyx appears to be a sensitive

Modern resuscitation of hemorrhagic shock

marker of endothelial injury, and is stimulated by inflammatory and ischemic states. This breakdown can be visualized by electron microscopy, fluorescent antibody
staining, as well as intravital microscopy. Measurements
using these techniques in isolated organs and animals have
demonstrated complete denuding of the glycocalyx layer in
response to hemorrhagic shock and ischemiareperfusion
injury [1216]. Measuring plasma concentrations of glycocalyx components provides a less invasive means of
detecting its breakdown. Syndecan-1 (a backbone proteoglycan) has become one surrogate lab marker for nonspecific damage to the glycocalyx.
Using syndecan levels in human surgical patients, Rehm
et al. [17] demonstrated evidence of glycocalyx damage
secondary to ischemiareperfusion injury due to occlusion
of the aorta during open aneurysm repair. Serial measurements of syndecan-1 levels before, during and after surgery
showed a spike of syndecan-1 immediately after aortic
unclamping. After an average of 40 min of clamp time,
syndecan levels increased by 15 fold from a median
baseline level of 1.2 lg/dl (range 0.721.42).
The importance of glycocalyx damage in trauma is
unclear, but it appears to happen early after injury and
correlates with worse outcomes. Porcine models of traumatic brain injury and controlled hemorrhage show elevation in syndecan-1 levels within 15 min of injury [16].
Increased syndecan-1 levels have been documented in
prospective observations of human trauma patients. Johansson et al. [18] evaluated 75 patients across a wide
range of injury severity, and noted a median syndecan-1
level of 63 ng/ml (IQR 38-127). These patients were then
dichotomized as either above or below this median value,
with patients in the high syndecan group demonstrating
increased mortality (42 vs 14 %, p = 0.006). HaywoodWatson et al. [19] examined 32 patients presenting in
severe traumatic shock with an overall mortality rate of
44 %. Syndecan-1 levels in this group were markedly
elevated on admission (554 93 ng/ml), and trended
down after resuscitation. Patients with persistent elevations
in syndecan-1 after resuscitation showed a trend towards
increased mortality, but not at statistical significance in this
small patient group.
Glycocalyx protective strategies in animal models are
under investigation. These target either preservation of the
existing glycocalyx by preventing enzymatic breakdown or
repair of injury by resupplying the soluble components
through plasma transfusion. In isolated guinea pig hearts,
pretreatment with antithrombin or hydrocortisone prior to
ischemic or inflammatory insult has been shown to effectively protect the glycocalyx from breakdown (Fig. 1c)
[1315]. Transfusion of fresh frozen plasma in rats has also
shown restoration of denuded glycocalyx when compared
to crystalloid resuscitation [20].

Trauma-induced coagulopathy: endogenous causes

Severely injured trauma patients are at a high risk of
developing coagulopathy immediately after trauma, with
alterations in conventional coagulation tests seen in
1034 % of trauma patients immediately upon hospital
presentation [21]. Traditionally, this was understood to
develop as a combination of several simultaneous processes: loss of clotting factors via hemorrhage, hemodilution from resuscitation fluids, and dysfunction of the
remaining enzymes due to an increasingly acidotic and
hypothermic patient. The depth of understanding of this
trauma-induced coagulopathy has expanded, and requires
changes to the traditional model. Numerous observational
studies of severely injured patients have added considerably to our understanding of the speed in which coagulopathy develops and what mechanisms are behind it
(Table 1).
While the administration of pre-hospital fluid is associated with coagulation abnormalities in a dose-dependent
fashion [22], trauma patients who have not received a large
amount of fluid remain predisposed to early coagulopathy
[23]. This coagulopathy is even found at the scene of
injury, before any intervention has occurred. As shown by
Floccard et al. [24], 56 % of severely injured patients
(n = 45, median injury severity score = 25, IQR 13-35)
were found to have abnormal coagulation results from
blood samples drawn prior to hospital arrival. This has led
to the redefinition of trauma-induced coagulopathy into
two components: Acute Coagulopathy of Trauma (ACoT)
and the Resuscitation-Associated Coagulopathy (RAC) to
distinguish between mechanisms stemming directly from
traumatic injury and those from iatrogenic causes [25].
This early hypocoagulability appears to be triggered by
the endothelial damage and cytokine release associated
with trauma, followed by the hypoperfusion and hypoxia of
shock. The evolutionary role of this seemingly counterintuitive reaction to trauma is hypothesized to be an attempt
by the host to maintain patency of critical vascular beds
during periods of low flow, but this locally helpful adaptation becomes harmful in the setting of severe injury and
hypoxia [26]. The responsible mechanisms for this include
activated protein C and release of endogenous heparins.
Considerable work has been done elucidating how
activated protein C (APC) is involved in the ACoT [21, 27,
28]. The first step in APC generation begins with the initial
hypoxia and release of inflammatory cytokines found in
traumatic shock, which leads to increased concentrations of
thrombomodulin (TM). The rise in TM concentration is
likely due to increases in membrane bound TM (from
preformed intracellular stores), or through shedding of
soluble TM into the circulation. As the availability of TM
increases, it binds thrombin, shunting thrombin away from

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D. T. Martin, M. A. Schreiber
Table 1 Current trials for initial resuscitation of traumatic hemorrhage
Investigative goal

Experimental arms

Setting

Study name

Appropriate ratio of plasma and

platelets to RBC transfusion

FFP:Platelet:RBC ratios
of 1:1:1 vs 1:1:2

Hospital

Pragmatic, randomized optimal

platelets and plasma ratios

Benefit of early use of plasma for

resuscitation

FFP vs Crystalloid for

initial resuscitation

Pre-hospital

A prospective, randomized
comparison of fresh frozen
plasma versus standard
crystalloid intravenous fluid as
initial resuscitation fluid

Benefit of early use of plasma for

resuscitation

Plasma vs standard care

for initial resuscitation

Pre-hospital

Pre-hospital air medical plasma

(PAMPer) phase III multicenter,
prospective, randomized, openlabel, interventional trial a 4-year
multicenter open-label
randomized trial

Utility of empiric fibrinogen

concentrates in a pre-hospital
setting.

Fibrinogen Concentrate
vs placebo

Pre-hospital

A multicenter double-blind,
placebo controlled, randomized,
pilot trial to assess the efficacy of
pre-hospital administration of
fibrinogen concentrate (FGTW)
in trauma patients, presumed to
bleed (FI in TIC)

Goal-directed clotting factor

replacement versus plasma
administration

Full factor replacement

(Fibrinogen
Concentrate,
prothrombin Complex
concentrates, FXIII
concentrate) vs FFP

Hospital

RETIC trial: reversal of traumainduced coagulopathy using

coagulation factor concentrates
or fresh frozen plasma

Utility of vasopressin in large

volume blood transfusion

Vasopressin vs saline
(bolus followed by
48 h infusion)

Hospital

AVERT shock: arginine

vasopressin during the early
resuscitation of traumatic shock

its procoagulant function of fibrin production and into

generation of APC. APC will then begin to cleave clotting
factors V and VIII, and block the inhibition of tissue
plasminogen activator (tPA) leading to plasmin-mediated
hyperfibrinolysis.
Much of the initial work on APC relied on the observation of decreasing levels of Protein C in association with
increasing levels of TM, and not on the actual detection of
APC in the serum of trauma patients [27]. However, more
recent observations have shown correlations between APC
levels and ACoT, as well as diminished levels of coagulation factors V and VIII (APC targeted factors) [28].
Another contributor to early coagulopathy is the release
of endogenous heparinoids. As discussed previously, the
endothelial glycocalyx is damaged early in trauma and
contains heparin sulfate in significant amounts within its
glycoprotein skeleton. Damage to the glycocalyx will lead
to shedding of these heparin particles, contributing to
ACoT. Prospective observational work by Ostrowski et al.
[29, 30] has shown a correlation between elevated syndecan-1 with ACoT, and demonstrated a 5 % rate of autoheparinization found immediately upon hospital
presentation. This work also demonstrated an association
between elevated syndecan-1 levels with increased

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concentration of soluble thrombomodulin and decreased

levels of protein C, showing autoheparinization and APC
pathways likely occur in tandem.
Beyond alterations in the early phases of the coagulation
cascade, decreased availability of fibrinogen and increased
fibrinolysis decrease the ability to quickly form a stable
clot. Depending on what lab value criteria are used and the
injury severity of the population, observational data have
shown that fibrinogen depletion (levels below 1 g/l) can be
found at rates of 5 % [31], and pathologic rates of fibrinolysis occur in 334 % of severely injured patients on
admission [3234]. Contributing factors to hyperfibrinolysis include acidosis and increased tPA activation of plasminogen. tPA activity is enhanced due to both increased
secretion from endothelial cells, and APC-related blockage
of tPA inhibitor.

Recent trends
Utilizing what we have learned regarding the ACoT and
the glycocalyx informs our understanding of the results of
recent trials regarding artificial fluids and the use of tranexamic acid (TXA) for the treatment of hemorrhagic shock.

Modern resuscitation of hemorrhagic shock

These trials support the use of TXA and permissive

hypotension during resuscitation, while weakening the
support for colloids and hypertonic saline.
Artificial colloids and hypertonic saline
Animal models of hemorrhage have shown hydroxyethyl
starch (HES) to be effective at restoring arterial pressures
at lower volumes than Ringers lactate (LR) [35], though
this blood pressure improvement has been associated with
an increase in bleeding from standardized liver injuries
[36]. Recent data from two studies in human trauma
patients, a single-center retrospective study and a small
single-center randomized trial, have shown potential benefit of HES use in penetrating trauma patients [37, 38].
However, repeated meta-analyses of randomized trials
comparing HES to other fluid therapy across many critically ill patient populations (with over 8000 patients
involved) have shown HES use to be associated with an
increased risk of the need for renal replacement therapy
(relative risk of dialysis 1.31 95 % confidence interval
1.161.49) [39]. The cause of this harmful impact on the
kidney, as well as other side effects of HES such as pruritus, is the uptake of the starch molecules into tissue
through cellular pinocytosis [40]. HES is absorbed in cells
(e.g. renal epithelial, liver parenchymal, endothelial cells),
and remains detectable in tissue over 1 year after administration [41].
Hypertonic saline showed significant promise as an
alternative to balanced crystalloid fluids due to its ability to
restore tissue perfusion at low volumes, modulate the
immune system [42], and to decrease intracranial pressures
in brain-injured patients [43]. Two recent multicenter trials
studying pre-hospital utilization of hypertonic saline have
been stopped due to safety concerns in trauma patients with
evidence of shock based on field vital signs [44], and for
futility in patients with blunt traumatic brain injury without
signs of shock [45]. These trials were run simultaneously,
each randomizing patients into one of three comparator
arms of small 250-ml fluid boluses of either 7.5 % hypertonic saline (HS), 7.5 % HS with 6 % dextran (HSD) or
normal saline. This initial bolus of study drug was then
followed by standard fluid treatment with isotonic crystalloids or blood products.
In the hypotensive trauma patient trial [44], 895 patients
were randomized prior to premature cessation of the study.
Those subsequently treated with both HS (n = 220) and
HSD (n = 256) exhibited higher admission sodium levels
than saline (n = 376)-treated controls (sodium levels 147.1
and 147.8 vs 139.5, p \ 0.001), but this did not lead to a
mortality benefit (28 day survival among HS-73.0 %,
HSD-74.5 %, NS-74.4 %, p = 0.91) or differences in other
outcomes of interest such as ARDS-free survival. When

patients were further stratified into groups based on initial

24-h blood transfusion volumes, the patients in the HS and
HSD groups who had not received a blood transfusion
exhibited a higher mortality than saline controls (HS12.2 %, HSD-10.0 %, NS-4.8 %, p \ 0.001), leading to
cessation of the trial. Roughly two-thirds of those early
deaths occurred within 6 h of admission. Possible reasons
for this elevated risk of early death were increased bleeding
rates caused by the use of HS/HSD, or delayed recognition
by the treatment team of the need for blood transfusion due
to transitory physiologic improvements generated by
infusion of HS/HSD.
Given the current evidence for both artificial colloids
and hypertonic saline, their use outside of clinical trials is
not recommended. Though in austere environments such as
the battlefield, the benefits of the reduced volume enabled
by these agents may continue to outweigh other concerns.
Tranexamic acid
Tranexamic acid (TXA) is an antifibrinolytic medication
that works through plasmin inhibition to stabilize formed
blood clots. The use of this lysine analog was shown to
improve survival in the CRASH 2 trial, a multicenter,
randomized, placebo controlled trial with over twenty
thousand patients enrolled (n = 20,211). Use of TXA
demonstrated a reduction in 28 day mortality (14.5 %
compared to 16.0 %, p = 0.0035), though this benefit was
seen only when given within 3 h of injury. No increase in
thrombotic complications was seen [46, 47]. A subsequent
retrospective review of TXA use in the military in the
MATTERs study found a similar benefit, with unadjusted
mortality rates in treated (n = 293) vs untreated patients
(n = 603) of 17.4 vs 23.9 %, p = 0.03 [48].
Delayed resuscitation
Strategies that favor permissive hypotension over aggressive fluid resuscitation continue to show a survival
advantage. This was demonstrated in 1994 when hypotensive patients with penetrating wounds to the torso were
randomized in the field to receive standard crystalloid
resuscitation (n = 309) vs no fluids until hemorrhage was
controlled (n = 289) [49]. The average amount of prehospital fluid given to the standard treatment group was
870 667 ml, compared to 92 309 ml in the no fluid
group. While slightly higher systolic blood pressures were
found on admission in the pre-hospital fluid group
(79 46 vs 72 43 mmHg, p = 0.02), their platelet
counts were significantly lower, while PT and PTT were
significantly prolonged. No difference in blood product
transfusion volume was seen between each arm, but the no
fluid group demonstrated a higher overall survival rate

123

D. T. Martin, M. A. Schreiber

compared to the standard resuscitation group (70 vs 62 %,

p = 0.04).
More recent work by Dutton et al. [50] and Morrison
et al. [51] to define a minimum acceptable blood pressure
during active hemorrhage have shown similar results.
These two trials randomized patients to resuscitation
strategies targeting higher or lower blood pressure goals
(Duttonsystolic blood pressure of 100 vs 70 mmHg,
Morrisonmean arterial pressure of 65 vs 50 mmHg) until
definitive control of bleeding was achieved. Neither trials
demonstrated a survival advantage for the higher blood
pressure targets, and Morrison et al. showed a significant
reduction in intraoperative blood transfusion volumes in
the hypotensive arm (1,594 2,292 vs 2,898 3,299 ml,
p = 0.03). In both studies, the actual differences in blood
pressure between the treatment groups were small, demonstrating that compensatory mechanisms often result in
spontaneous elevations in blood pressure in the absence of
aggressive fluid resuscitation.
These results are not generalizable to all trauma populations, particularly head-injured patients. The patient
populations in these hypotensive studies were predominately penetrating trauma, and Dutton et al. excluded
central nervous system injury. In light of the fact that
hypotension is a primary predictor of bad outcomes in head
injury patients, the potential benefits of permissive hypotension in the head-injured population have not been
studied.

Future interventions
Earlier use of plasma
Plasma as a resuscitation fluid offers numerous advantages.
A potent intravascular fluid expander, it reduces the risk of
dilutional coagulopathy by providing a balanced mix of
procoagulant and anticoagulant factors. It also appears to
have protective effects on the endothelial glycocalyx border in animal and in vitro models, providing a mechanism
for decreasing fluid extravasation and edema formation.
Hyperpermeability can be induced in vitro with human
umbilical vein endothelial cells through ischemiareperfusion injury. This hyperpermeability is found to persist
after resuscitation with LR, while cells treated with fresh
frozen plasma (FFP) exhibit less permeability than even
that of uninjured control cells [19]. Kozar et al. [20]
demonstrated similar findings in a rat model of hemorrhagic shock. Using controlled hemorrhage to generate
shock resulted in the loss of the glycocalyx (as seen on
immunostaining and electron microscopy). LR did not
change this loss, while resuscitation with FFP led to substantial restoration of the glycocalyx. Possible mechanisms

123

behind this ability to repair/reform the glycocalyx include

resupplying soluble plasma components to the luminal side
of the glycocalyx and stimulation of syndecan replacement,
either through increased synthesis or release of intracellular
stores. This restorative property may lead to improved
vascular tone, reduced edema formation, and treatment of
the endothelial components of the acute coagulopathy of
trauma.
Numerous studies have addressed the most appropriate
role for plasma in the acute resuscitation of trauma. Retrospective data from the military among massively transfused patients (receiving C10 units of pRBCs in 24 h)
demonstrated a survival benefit in patients receiving higher
ratios of FFP to RBC units, with a mortality of 65 % in the
lowest ratio group (FFP:RBC of 1:8) improving to 19 % in
the highest ratio group (FFP:RBC of 1:1.4), p \ 0.001
[52]. Similar results have been found in civilian retrospective reviews [53, 54].
These retrospective evaluations regarding plasma
transfusion are difficult to interpret as they cannot rule out
a survival bias influencing the supposed benefits of higher
plasma ratios. Survival bias may occur because RBCs are
typically more readily available than plasma, so patients
must survive in order to achieve a high ratio of plasma to
RBCs. It is unclear if patients survive because they receive
a high ratio or they receive a high ratio because they survive long enough for plasma to become available.
Prospective observational data collected as part of the
PROMMTT study also provides support for the early
application of plasma in a high ratio. In this multicenter
study, data were collected from 1,245 trauma patients
across ten level I trauma centers in the United States, all of
whom received blood products within 6 h of admission.
Real-time recording of administration time and volumes of
blood products was performed [55]. In a subset of patients
who received a minimum of three units of blood, median
time to death from hemorrhage was 2.6 h, and a survival
advantage was seen in those who received higher ratios of
plasma to RBCs. The survival advantage provided by
higher ratios of plasma was greatest when it was achieved
in the first 6 h of treatment, as compared to patients who
received more plasma later in their resuscitation [56, 57].
Better quality evidence involving the optimal ratio of
plasma to RBC transfusion in severe trauma has been
collected as part of the PROPPR (Pragmatic Randomized
Optimal Platelet and Plasma) trial and will soon be available (www.clinicaltrials.gov identifier: NCT01545232). In
this multicenter study, patients transfused one unit of blood
within 1 h of hospital arrival and who were predicted to
require a massive transfusion were randomized to a
Plasma:Platelet:RBC ratio of either 1:1:2 or 1:1:1. The
results of this trial, which has reached its enrollment goal,
will provide level one data regarding the utility of

Modern resuscitation of hemorrhagic shock

increased plasma and platelet ratios in the setting of massive transfusions.

Based on the available retrospective and prospective
data, pre-hospital use of plasma is beginning in certain
areas. Helicopter crews supplied with thawed plasma utilize protocols for its administration based on evidence of
shock or coagulopathy, with some preliminary data available. In a retrospective review consisting of 9 transfused
patients vs 50 controls [58], pre-hospital use of plasma
enabled transfusion to occur an average of 2 h earlier than
hospital transfusion. Though a higher overall mortality was
seen in the pre-hospital plasma group (56 vs 18 %,
p = 0.023), outcome results from this small nonrandomized trial are not widely generalizable.
While pre-hospital plasma transfusion in the treatment
of the severely injured has multiple potential benefits, its
superiority as a first-line agent in hemorrhagic shock has
not yet been proven. Any blood product transfusion carries
risk, and the administration of plasma to patients who
require only small volume red cell transfusion has been
retrospectively associated with increased pulmonary complications [59]. To better investigate the utility of early
plasma use, prospective randomized trials of pre-hospital
use of FFP are beginning. In one such trial (COMBATControl of Major Bleeding After Trauma), trauma patients
with physiologic signs of shock will be randomized by
ambulance crews to receive either standard crystalloid
treatment or plasma thawed on site in rapid fluid warming
baths [60].
Increased role of real-time coagulation monitoring,
activated clotting factors and fibrinogen concentrates
Given that prompt control of bleeding is required in hemorrhagic shock, the rapid restoration of a functional coagulation system is paramount. Clotting factors and
fibrinogen levels have been shown to quickly become
deficient among the severely injured. Even a balanced
transfusion of blood components in a 1:1:1 fashion may not
be able to provide sufficient quantities of factors like
fibrinogen, and may thus contribute to further hemodilution. Supplementation of these clotting factors through the
delivery of concentrated forms of fibrinogen and other
activated clotting factors in various combinations has been
investigated for use in trauma.
Empiric use of fibrinogen and factor VII
Empiric factor repletion with recombinant activated factor
VII (rFVIIa) has been attempted. Its use in a porcine model
of uncontrolled hemorrhage demonstrated improvement in
survival times and decreases in blood loss when combined
with hypotensive resuscitation strategies utilizing saline

infusion [61]. In humans, a randomized, placebo controlled

trial of rFVIIa in trauma patients with persistent bleeding
after initial resuscitation (the CONTROL trial) was stopped
for futility after enrolling 573 out of a planned 1,502
patients [62]. In this trial, 3 doses of rFVIIa were given
over a 4-h period to patients with active bleeding who had
received over 4 units of blood. Blunt and penetrating
patients were randomized separately. No difference in
30 day mortality was seen (mortality in blunt trauma:
11.0 % rFVIIa vs 10.7 % placebo, p = 0.93; in penetrating
trauma: 18.2 % rFVIIa vs 13.2 % placebo, p = 0.40), but
the use of rFVIIa was associated with a decreased volume
of transfused RBCs and FFP, as well as a trend toward
decreased ARDS development in the blunt trauma group
(3.6 % rFVIIa vs 7.2 % placebo, p = 0.08). Retrospective
data from the US militarys use of rFVIIa did not demonstrate a survival benefit or a reduction in massive
transfusion requirement between 266 soldiers treated with
rFVIIa and matched controls, though physician bias in the
use of rFVIIa confounded the study [63].
Use of fibrinogen concentrate is recommended when
levels are found to be under 150 mg/L [64]. As hypofibrinogenemia has been found in a high rate among the
severely injured [31], the empiric use of fibrinogen concentrate early in trauma may be of benefit. The use of
fibrinogen supplementation in trauma was examined in a
retrospective analysis of 252 patients who received a
massive transfusion in a military setting. Calculation of
fibrinogen transfusion was performed using estimates of
fibrinogen contents in all blood products given (ranging
from \100 mg per unit pRBCs, 400 mg per unit FFP, and
up to 2,500 mg in cryoprecipitate). This demonstrated a
survival advantage in patients given a ratio of fibrinogen:pRBCs of over 200 mg:1 unit during resuscitation
(Mortality rate 24 vs 52 %, p \ 0.001) [65]. Better data
are currently accruing in a pre-hospital trial in which
blunt trauma patients with evidence of bleeding and
physiologic signs of shock are randomized to placebo or
fibrinogen concentrate (www.clinicaltrials.gov identifier:
NCT01475344).
Prothrombin complex concentrate and fibrinogen
concentrate
In place of empiric therapy, more sophisticated correction
of factor deficiency is possible due to the increased use of
whole blood coagulation tests such as thromboelastography
(TEG) and rotational thromboelastometry (ROTEM).
These viscoelastic tests provide comprehensive monitoring
of clotting function, with measurements of time to initial
clot formation, fibrin polymerization rate, maximum clot
strength and fibrinolysis rates provided. This enables specific deficiencies in the coagulation process to be detected

123

D. T. Martin, M. A. Schreiber

in real time, thereby directing treatment for factor

supplementation.
Prothrombin Complex Concentrate (PCC) consists of
the vitamin K-dependent factors II, VII, IX and X, and low
volumes of anticoagulant enzymes protein C, protein S,
and antithrombin. PCC is commonly used for warfarin
reversal or treatment of bleeding in hemophilia [66, 67].
These agents carry a dose-dependent risk of thromboembolic events and the development of disseminated intravascular coagulation (DIC) [68]. In Austria, the use of PCC
along with fibrinogen concentrates is preferred over plasma
transfusion in trauma, and they are given in response to
measured abnormalities in ROTEM testing.
Current data regarding the utility of this targeted factor
replacement over plasma treatment in trauma are limited to
retrospective data. An initial study compared 80 patients at
a single Austrian institution treated solely with PCC/
fibrinogen to 601 patients from Germanys National
Trauma Database treated with plasma. The study demonstrated reduced blood transfusion volumes in the factortreated patients and equivalent mortality between groups
[69]. A subsequent retrospective analysis of prospectively
gathered data within a single institution compared 66 PCC/
fibrinogen-treated patients to 78 patients initially treated
with PCC/fibrinogen but who went on to receive plasma.
This study also showed a reduction of blood transfusion
volumes in the factor only group, again with no mortality
difference [70]. While demographic data between groups in
each study were similar, both of these analyses relied on
separating patients treated solely with PCC/fibrinogen from
those who went on to receive plasma, entering a source of
bias into the results.
The correction of coagulopathy through specific factor
supplementation is of significant potential benefit, particularly in patients sensitive to volume overload from plasma
(elderly, heart failure). However, the available data
regarding the use PCC and fibrinogen concentrates in
trauma has not shown a large enough benefit to justify the
increased risk of thromboembolic events and DIC they
pose. Recommendations for the use of these factors early in
the resuscitation of bleeding patients favor restricting them
to reversal of Vitamin K antagonists [64]. Further data is
currently being collected in a prospective, randomized trial
(the RETIC trial: www.clinicaltrials.gov identifier:
NCT01545635), that will provide head-to-head comparisons between the use of PCC/Fibrinogen/Factor XIII concentrates versus plasma transfusion in trauma patients
presenting with laboratory measurements of coagulopathy.
Systemic changes to current blood banking
Alternatives to current methods of blood component storage and transfusion exist. Cryopreservation of RBCs and

123

platelets has been explored for years, and is currently utilized by such groups as the Netherlands military to provide
blood component therapy in austere environments where
constant replacement of expired units is impractical [71].
To improve the availability of plasma, several options
exist. Liquid plasma has never been frozen and is used in
some high-volume trauma centers, and freeze drying
plasma to create lyophilized plasma (LP) has also been
used to circumvent storage requirements and availability
concerns. The use of whole blood has a long history in the
military, and provides a walking blood bank that avoids
the storage needs of blood components.
Freeze-dried plasma
Plasma is predominately stored as a frozen product, but this
limits its immediate availability in patients with hemorrhagic shock. Thawing of frozen plasma may take over
30 min, preventing an early balanced resuscitation and
contributing to a worsening dilutional coagulopathy. Prethawed plasma and liquid plasma are possible solutions,
but will lead to degradation of the product (including its
endothelial restoration benefits) over time [72], and are not
feasible away from high-volume centers.
Freeze-dried plasma is produced through dehydration of
donated plasma into a temperature stable powder. When
needed, it can be reconstituted with sterile water and
administered within minutes. Originally used by the US
military in the Second World War it was abandoned due to
viral transmission caused by the pooling of thousands of
individual plasma donors. However, with better screening
of donors, reduced size of donor pools and modern pathogen inactivation processes, it is considered safe for
transfusion and is currently used in military settings [73].
Reconstituted lyophilized plasma has been shown to have
better factor function than thawed plasma in vivo [74].
In vitro analysis has shown that the protective endothelial
properties of plasma are also preserved [75]. The benefits
of LP include its relatively long storage capacity at a broad
range of temperatures, its light weight (for use in military
settings), and its rapid availability for use.
Retrospective data regarding the utility of LP in a
French combat support hospital in Afghanistan revealed
ease of use and improvements in coagulation markers
among recipients [76]. Combat-relevant animal models
have demonstrated improved hemostatic efficacy and
reduction in dysfunctional inflammation and oxidative
damage compared to FFP, as well as the ability to reduce
the fluid volume used to reconstitute the plasma [74, 77].
This enables the creation of a hypertonic plasma product
requiring only half the volume of the original donated
plasma, but containing the same clotting factors as the
original volume. Lyophilized plasma is available for use in

Modern resuscitation of hemorrhagic shock

several European countries including France and Germany

but it is not FDA approved in the US. The French product
is currently being used in military operations in Afghanistan [78].
Widespread utilization of lyophilized plasma would
enable practical administration of plasma in austere settings and faster transfusion in the hospital. This would be
of benefit in both civilian and military settings to ensure a
high ratio of plasma transfusion. Currently, its widespread
adoption will require more trials demonstrating its safety
and efficacy.
Modified whole blood transfusion
Splitting donated blood into its separate components is
efficacious in managing the different half-lives of each
element, as well as in tailoring transfusions to meet the
specifications of each individual patient. However, given
that current massive transfusion protocols often attempt to
recreate the initial product, the use of whole blood in the
setting of hemorrhagic shock may provide benefit.
The transfusion of fresh whole blood has been employed
by the military for a century, with 1020 % of patients in
Afghanistan and Iraq receiving whole blood as a portion of
their resuscitation [79, 80]. Fresh WB provides a resuscitative fluid containing a complete set of coagulation factors, fibrinogen, functional platelets and normal
hemoglobin, and is therefore superior to the product produced by recombining the individual components of fractionated blood [79]. In an austere environment, the
walking blood bank may be more accessible than stored
blood products.
Retrospective evaluation of recent military use of WB
has shown its utility, as compared to component-based
therapy. Spinella et al. compared patients injured in
combat who had received WB as part of their resuscitation (n = 100) to those who had received complete
component therapy (RBC, plasma, and platelets;
n = 254). This excluded patients who received only
RBCs and plasma as well as those who received both WB
and complete component therapy. A survival advantage
was found for the WB group (30 day survival: 95 vs
82 %, p = 0.002) despite similar admission hemodynamic and laboratory parameters [81]. Perkins et al. [82]
made the same retrospective comparison among massively transfused patients, but found equivalent survival
between groups (85 treated with WB vs 284 with complete component therapy). The rate of ARDS among the
WB group was over twice that of the component therapy
group (18.8 vs 7.4 %, p = 0.002) suggesting the potential
for harm. This study is limited by the fact that one-third
of the patients were lost to follow-up approximately
1 week after initial resuscitation.

A single-center, randomized trial was recently completed within the United States which examined the efficacy of modified whole blood (mWB) [83]. Patients with
active bleeding requiring emergent transfusion were randomized to receive component therapy in a 1:1:1 fashion,
versus leukoreduced whole blood. As the leukoreduction
process used in this study also removed platelets from the
WB, one pack of apheresis platelets was given for every six
units of mWB. A total of 107 patients were randomized, 77
of whom received study products per protocol. No significant difference in mortality was found between the per
protocol groups (30 day mortality 27 % mWB vs 15 %
Component therapy, p = 0.16), though a small reduction in
transfusion requirements was seen in the mWB group when
patients with traumatic brain injury were removed from the
analysis.
Barriers to civilian WB use include the decreased shelf
life, donor pool requirements, and the increased potential
of a transfusion reaction that WB presents. Type O donors
possess varying levels of antibodies against AB blood
antigens, which presents a small risk to patients when AB
incompatible WB is transfused (from an O- donor to an A?
or B? recipient). This risk is almost completely absent
when individuals with known high titers of AB antibodies
are excluded from the donor pool [84]. Improved leukoreduction methods allow platelet retention in WB, mitigating the need for supplemental platelet transfusion [85],
and the shelf life of whole blood may be underestimated,
with some data showing adequate retention of platelet
function for 10 days post collection [86]. Finding the
appropriate role of WB, and the ability to incorporate it
into the current blood banking infrastructure, will require
further investigation.

Adjuncts to fluid and factor replacement

Blood transfusion, judicious crystalloid use and expeditious control of bleeding are critical in treating hemorrhagic shock. The addition of agents addressing other
aspects of shock physiology has long been explored. Use of
vasopressin, specific DNA targeting medications, and
antioxidants will be discussed.
Arginine vasopressin
Vasoactive agents have been examined in both animal
models of hemorrhagic shock and in the trauma population.
While clearly indicated for the treatment of hypotension in
the setting of euvolumia, accumulating evidence shows that
vasopressors, specifically arginine vasopressin, may be of
benefit early in hemorrhagic shock. This benefit may be
seen even before volume replacement has been achieved.

123

D. T. Martin, M. A. Schreiber

Arginine vasopressin is made in the hypothalamus. It is

released in response to reduced blood pressure or increased
plasma osmolality. It acts through several mechanisms
including modulation of nitric oxide and binding to V1
receptors on vascular smooth muscle [87]. Vasopressin
increases blood pressure in shock states, but excessive
serum concentrations of vasopressin do not result in
extreme elevations of blood pressure [88]. Vasopressin also
remains functional in a low pH environment and helps
smooth muscle cells maintain cytosolic calcium levels,
making it more effective in the physiologic conditions
found during acute hemorrhagic shock [89].
Traumatic injury and blood loss cause an immediate
compensatory release of endogenously created catecholamines and vasopressin into the serum [90, 91]. This release
contributes to the initial vasoconstrictive nature of hemorrhagic shock, and works to restore tissue perfusion via
increased blood pressure and increasing the circulating
volume through venoconstriction. In severe hemorrhagic
shock endogenous stores of vasopressin may be insufficient
to sustain vascular tone [92]. Loss of vasopressin through
hemorrhage and subsequent fluid dilution can lead to a
vasopressin-deficient state. This deficiency may contribute
to hemorrhagic shock that is unresponsive to fluid
administration.
Morales et al. [92] showed that canines subjected to
prolonged hemorrhagic shock became unresponsive to fluid
resuscitation but administration of vasopressin restored
cardiovascular tone and function. In porcine models of
uncontrolled liver hemorrhage and shock, hemodynamic
parameters have been successfully normalized without any
fluid administration by the application of vasopressin.
Comparing vasopressin to epinephrine or saline resuscitation in this model demonstrated improved survival and
decreased total blood loss in swine treated solely with
vasopressin [9395]. When arginine vasopressin was used
in conjunction with LR, the treated swine required
decreased fluid volumes during early resuscitation [96].
The benefits of early vasopressin use are faster restoration of tissue perfusion and reduced fluid requirements
to achieve it. The risks of treating hemorrhagic shock
with vasopressin in a heterogeneous trauma population
include cardiovascular complications and the potential of
masking hypovolemia leading to cardiovascular collapse.
The safety of utilizing vasopressin and other vasopressors
early in the treatment of hemorrhagic shock has been
questioned based on several retrospective studies [97,
98]. These studies revealed that early treatment with
vasopressors was associated with increased mortality;
however, vasopressor-treated patients were more significantly injured, required more operations, and received
more blood products than patients who did not receive
vasopressors. Beyond such confounders (which were

123

acknowledged by the authors) these studies are limited by

their exclusion of early deaths (defined in the studies as
death before 24 or 48 h), which is a time frame of interest
in patients with vasopressin-deficient shock states following hemorrhage.
A prospective, randomized study evaluating the use of
arginine vasopressin in 78 trauma patients was performed
at a single center [99]. Trauma patients with a systolic
blood pressure under 90 mmHg received an initial bolus of
study drug within 1 h of their initial hypotensive event,
followed by a 5-h infusion. The infusion was held or
reduced if systolic blood pressure increased over
160 mmHg. The vasopressin group received less total fluid
over the first 5 days of hospitalization compared to controls
(13.2 9.8 vs 16.0 12.8 l, p = 0.03), but no significant
difference in 30 day mortality was found between groups
(34.2 % in the vasopressin group vs 27.5 % in the control
group, p = 0.521).
To better clarify the role of vasopressin in trauma
resuscitation, more work is needed. Though its use as an
adjunct to fluid replacement appears safe in the singleinstitution trial cited above, only a small benefit in reducing
fluid administration was found. Current research consists of
an ongoing trial (AVERT Shock-www.clinicaltrials.gov
identifier: NCT01611935) which is randomizing trauma
patients who receive at least 6 units of blood within 12 h of
admission to vasopressin or placebo. Those randomized
will receive a bolus of vasopressin or placebo followed by
a 48-h continuous infusion targeting a mean arterial pressure of 65 mmHg.
Immune modulation: antioxidants
The oxygen debt that develops during shock generates a
large reperfusion response as homeostasis is restored.
Endothelial cell damage and glycocalyx destruction provide a substrate for primed leukocytes to adhere to and
transmigrate into tissue. Release of TNF-a and other
cytokines leads to further leukocyte activation and generation of reactive oxygen species. Oxidative stress both
increases the inflammatory response and worsens shock
states. This generates the early SIRS response seen in
trauma patients with associated vasodilation that can result
in multiorgan failure.
Immune-modulating medications may help reduce the
intensity of this response. Many potential options are under
investigation, and their benefits should be weighed against
their inherent risks. Use of activated Protein C for septic
shock was halted after further testing showed no benefit in
28 day survival to justify its risk of bleeding [100]. Medications with more benign side-effect profiles such as
glutamine or ascorbic acid (AA) may prove useful as
adjuncts.

Modern resuscitation of hemorrhagic shock

AA regulates microvascular function through free radical scavenging and modulation of nitric oxide levels [101].
Deficiencies in AA have been found in critical illness,
contributing to vascular dysfunction [102]. High-dose AA
administration in severe burn patients ([30 % total body
surface area) has led to significantly reduced fluid
requirements during initial resuscitation when compared to
placebo (3.0 1.7 vs 5.5 31 l, p \ 0.01) [103]. Use of
antioxidants in the post-resuscitation treatment of trauma
patients has also been associated with improved outcomes.
Initiation of high-dose antioxidant regimens (including
AA) upon admission to a trauma ICU has been shown to
result in a reduction in mortality among treated patients
(n = 2,272) compared to historical controls (n = 2,022)
(mortality rate 6.1 vs 8.5 %, p = 0.001), as well as
reductions in complications such as surgical site infections
and ventilator dependence [104, 105]. A randomized trial
of AA and alpha tocopherol supplementation among 542
trauma patients and 53 surgical patients demonstrated less
robust results, with only a non-significant trend towards
reduction in ARDS/pneumonia rates (relative risk reduction 0.81 with a 95 % confidence interval 0.601.1) [106].
Use of antioxidants such as ascorbic acid in the immediate stabilization period of traumatic shock may prove
beneficial through preservation of vascular tone and
reduction of inflammation. In animal models, the early
addition of AA to resuscitative fluids used during hemorrhagic shock has been associated with reductions in IL-6
production and oxidative DNA damage [77, 107]. This was
seen when AA was used as a pH buffer for lyophilized
plasma, with citric acid and hydrochloric acid as comparators. Further study is needed to determine whether or not
the addition of antioxidants early in resuscitation will
translate into significant outcome benefits.
DNA modulation
Trauma induces large-scale changes in host DNA expression. Comparisons of mRNA concentrations in leukocytes
between a small number of healthy controls and trauma
patients have demonstrated alterations of transcription
frequency (either up or down) in approximately 80 % of
the leukocyte genome [108]. These changes were found to
occur in all trauma patients regardless of injury severity or
shock state. Splitting this patient group into cohorts defined
by the length of their hospital course has shown that different genetic expression patterns can be correlated with
some basic patient outcomes [109].
It is unknown to what extent these genomic changes
reflect a spectrum of normal host reactions to increasing
injury severity, complications encountered in recovery, or
individual variations in response to trauma. It is conceivable that there is a subset of patients who are genetically

prone to generate a more intense and prolonged inflammatory response to traumatic injury than the general population. This genetic predisposition may lead to poorer
outcomes in this group.
The potentially maladaptive genetic changes that occur
in response to trauma may be caused by pathologic
derangements in DNA regulation. Basic science investigation into potential mechanisms of this has shown that
upregulation of histone deacetylases (HDAC) occurs in
response to ischemiareperfusion injury [110]. HDACs are
a large family of proteins that regulate chromatin structure
by removal of acetyl groups from histone complexes. Local
deacetylation of chromatin results in DNA condensing and
subsequent silencing of gene transcription. This is opposed
by the action of histone acetyltransferases (HATs) which
promote chromatin unraveling and allow transcription
factors to access the genome [111]. In normal conditions
HDACs and HATs operate in tight balance, but the
increase in HDAC activity after trauma disturbs this.
Medications that inhibit HDAC activity may minimize
this unbalance and alter the hosts genetic response to acute
injury. This would hopefully improve the hosts ability to
tolerate trauma by generating a prosurvival phenotype
[112]. Valproic acid (VPA), typically used as an anticonvulsant, is one potential HDAC inhibitor that is in early
stages of investigation for this use. In rat models of controlled hemorrhage, use of VPA has resulted in dosedependent changes in histone acetylation rates, as well as
significant early survival improvements when compared to
no treatment [113, 114].
Use of VPA in porcine models has shown mixed results.
Different models of injury used in these investigations have
included controlled hemorrhage followed by prolonged
aortic clamping, polytrauma involving liver laceration and
femur fracture, and traumatic brain injury coupled with
controlled hemorrhage. Use of VPA in these situations has
altered endothelial gene expression, decreased pathologic
scores of tissue injury, decreased fluid requirements, and
increased levels of protective cellular protein families such
as the Heat shock, b-catenin and Bcl-2 proteins [115117].
When used in a traumatic brain injury model as an adjunct
to hetastarch or plasma resuscitation, the addition of VPA
demonstrated significant reductions in measurements of
brain swelling and size of intracranial lesion in the acute
setting [118, 119]. VPA also appears to improve early
survival after traumatic shock when compared to no
treatment during short observation periods of 46 h after
injury [115].
A longer observation period has not shown a benefit of
VPA use. Extending the resuscitation/recovery period to
24 h after hemorrhage and ischemic injury (via aortic
clamping), demonstrated worse outcomes in VPA-treated
swine compared to controls [120]. Swine treated with VPA

123

D. T. Martin, M. A. Schreiber

as either a single dose or with one redosing at hour 12

exhibited earlier mortality (12.6 vs 15.8 h, p \ 0.02) and
required more fluid and vasopressor support than controls.
Invasive cardiac monitoring during the resuscitation period
demonstrated decreased cardiac output and increased pulmonary capillary wedge pressures in VPA-treated animals.
A possible limitation of this study was the lack of blood
product transfusion in the resuscitation phase, given that
the extreme severity of the injury made the model uniformly fatal across all groups.
Our understanding of the genetic changes that occur in
trauma is incomplete, and the study of epigenetic therapy
through medications such as VPA is in its early stages.
While decreased survival has been demonstrated in severe
injury with inadequate resuscitation, epigenetic therapy as
an adjunctive treatment is still under investigation. Further
animal modeling is needed before the safety and utility of
creating a survival phenotype can be considered in the
treatment of traumatic shock.

Conclusion
Beyond prompt control of bleeding, the optimal management of hemorrhagic shock is unclear. Results from
large clinical studies have shown utility in the use of
tranexamic acid and permissive hypotensive resuscitation
strategies, while the existing work on hypertonic saline
and artificial colloids does not support their use in the
initial resuscitation of the trauma patient over traditional
crystalloid therapy in a civilian setting. The empiric use
of activated Factor VII alone has not shown a significant
benefit.
Advances in knowledge regarding the endothelial and
enzymatic responses to hemorrhagic shock are accumulating and are guiding much of the current clinical investigative work in initial resuscitation. Immediate transfusion
of plasma appears to have great potential in the severely
injured, though the extent of its clinical impact is not
proven. Optimization of blood transfusion strategies continue, soon to be augmented with the results of the
PROPPR trial. The utility of repleting multiple clotting
factors, either empirically or goal-directed, is under
investigation in several small studies, as are the possible
additions of vasopressin, Valproic acid, and various antioxidant infusions. Further work in modifying blood transfusion through different storage techniques (lyophilized
plasma, refrigerated whole blood) may improve the safety
profile and clinical utility of such products. Until more data
is adequately gathered, initial resuscitation strategies will
vary depending on available resources and local
preferences.

123

Conflict of interest
David Martin and Martin Schreiber declare that they have no
conflict of interest.
Ethical standards This review article does not present any original
data from studies with human or animal subjects performed by any of
the authors.

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