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DOI 10.1007/s00068-014-0416-5
REVIEW ARTICLE
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
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
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
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].
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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
FFP:Platelet:RBC ratios
of 1:1:1 vs 1:1:2
Hospital
Pre-hospital
A prospective, randomized
comparison of fresh frozen
plasma versus standard
crystalloid intravenous fluid as
initial resuscitation fluid
Pre-hospital
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)
Hospital
Vasopressin vs saline
(bolus followed by
48 h infusion)
Hospital
123
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.
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D. T. Martin, M. A. Schreiber
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
123
D. T. Martin, M. A. Schreiber
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
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.
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D. T. Martin, M. A. Schreiber
123
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
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D. T. Martin, M. A. Schreiber
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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