REVIEW

CURRENT
OPINION Advances in hemorrhage control resuscitation
Maeve Muldowney a, Pudkrong Aichholz a, Rajen Nathwani a,
Lynn G. Stansbury b, John R. Hess c, and Monica S. Vavilala a,b

Purpose of review
Despite significant advances in trauma management over the last twenty years, uncontrolled hemorrhage
remains the leading cause of preventable death in trauma. We review recent changes affecting
hemorrhage control resuscitation.
Recent findings
Early blood product usage has become well established as a standard of care in trauma hemorrhage
control. To enable this, low titer group A liquid plasma and group O whole blood are increasingly utilized.
Single donor apheresis platelets have now replaced pooled donor platelets in the USA and are often
pathogen reduced, which has implications for trauma resuscitation. Further work is examining timing and
dosing of tranexamic acid and the debate in factor concentrate usage in trauma induced coagulopathy
continues to evolve. The ‘Stop the bleed’ campaign has highlighted how important the use of hemostatic
dressings are in hemorrhage control, as too is the expanded use of endovascular aortic occlusion. We
highlight the ongoing research into desmopressin use and the undetermined significance of ionized calcium
levels in trauma. Finally, we discuss our own hospital experience with coagulation testing and the paucity
of evidence of improved outcomes with viscoelastic testing.
Summary
Improving trauma coagulopathy diagnostics and hemorrhage control are vital if we are to decrease the
mortality associated with trauma.
Keywords
hemorrhage control resuscitation

INTRODUCTION LOW TITER GROUP A LIQUID PLASMA

Hemorrhage control resuscitation is a set of tools
and actions aimed at supporting perfusion and
minimizing the coagulopathy that accompanies
acute life-threatening bleeding. A cornerstone of
hemorrhage control resuscitation is the early and
appropriate use of blood products and blood
adjuncts, based on the recognition of an acute
coagulopathy of trauma and the inevitability of
dilutional coagulopathy during crystalloid resusci-
tation. By 2007, resuscitation guidelines were advo-
cating 1 : 1:1 ratios of blood components [1] and this
approach has been validated in subsequent large-
scale trials [2,3].
Despite these advances, uncontrolled hemor-
rhage remains the leading cause of preventable
death following trauma [4]. Males and those from
low- and middle-income countries remain dispro-
portionally affected [5].
In this review, we summarize eight areas of
active research and debate shaping the prehospital
and bedside approach to hemorrhage control resus-
citation.
AND LOW TITER GROUP O WHOLE BLOOD
The development of safety data on never-frozen
plasma and efforts to incorporate low-titer group
A liquid plasma into prehospital and hospital care
&
advances slowly but steadily [6,7 ]. Of the 188 Level
1 trauma centers in the USA, half now use group A
plasma to supplement the limited supplies of ‘uni-
&
versal donor’ AB plasma [8 ]. Group A donors are 10
times more common than group AB donors and at
least 85% of older A donors have anti-B titers less
than 1 : 256. Identifying such donors and diverting
a
Department of Anesthesiology and Pain Medicine, Harborview Medical
Center, bHarborview Injury Prevention and Research Center and cDe-
partment of Laboratory Medicine and Pathology, Harborview Medical
Center, Seattle, Washington, USA
Correspondence to Maeve Muldowney, MB, BCh, BAO, Department of
Anesthesiology and Pain Medicine, Harborview Medical Center, 325 9th
Avenue, Seattle, WA 98104, USA. Tel: +1 206 817 4405;
e-mail: mmuldow@uw.edu
Curr Opin Anesthesiol 2022, 35:176–181
DOI:10.1097/ACO.0000000000001093

www.co-anesthesiology.com Volume 35  Number 2  April 2022

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 Advances in hemorrhage control resuscitation Muldowney et al.
KEY POINTS
 Changes in blood banking processes and regulatory
requirements are afoot, which have clinical implications
for patients and anesthesiologists should be aware of
these changes.
 Tranexamic acid reduces death from mild to moderate
traumatic brain injury.
 Exact role for factor concentrates in hemostatic
resuscitation, outside of warfarin reversal or specific
factor deficiency, is still under investigation.
 Use of desmopressin, calcium, and viscoelastic testing
has, thus far, not shown a mortality benefit in trauma.
 No evidence to suggest superiority of either fibrinogen
concentrate or cryoprecipitate in trauma resuscitation.
their plasma to make 26-day liquid plasma means
that this product can be available in larger quantities
and deployed to remote ambulance and helicopter
bases for longer than the 5 days allowed for thawed
plasma. The Prehospital Plasma during Air Medical
Transport in Trauma Patients at Risk of Hemorrhagic
Shock (PAMPer) trial supported the use of prehospi-
tal plasma for improving the 30-day survival of
patients at risk for hemorrhagic shock [9]. Liquid
plasma will increase its availability in the prehospi-
tal environment.
Thawing a unit of frozen plasma requires half an
hour in a water bath, time that can lethally limit the
immediate availability of plasma for resuscitation of
catastrophic bleeding [10]. Modern specialized
microwaves can reduce that time to 5 min.
The use of low titer group O whole blood in level
1 trauma centers in the USA is rising; approximately
one third of centers now carry this, up from 4 centers
&
5 years ago [8 ]. The advantages of a single bag
delivering a universal donor, balanced, concen-
trated hemostatic product without the requirement
for plasma thawing are obvious for both prehospital
&
[11 ] and hospital situations. Product availability
varies widely across institutions, so it remains criti-
cal that anesthesiologists know how to perform
hemostatic resuscitation with both whole blood
and conventional components and participate
actively in local discussions to ensure optimal use
&
[12 ].
CHANGES IN PLATELET PRODUCTS
Historically, one unit of platelets, as a separate blood
product component, was derived from one unit of
donated whole blood. These units were then com-
bined as pools of typically six units as one adult
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dose. Single whole-blood-derived units, as the basis
of the pooled product, were removed from blood
bank inventories in the summer of 2021 at the
direction of the Food and Drug Administration
because of their association with increased risk of
bacterial contamination [13]. All platelet units are
now derived from single donor apheresis and are six
times larger than the old whole-blood-derived units.
‘Balanced’ 1 : 1:1 transfusion is now accomplished
by 6 : 6:1 (six red cells, six plasma, and one apheresis
platelet unit), reflecting this change in collection
method.
All apheresis platelets are not equal in terms of
circulating platelet count and plasma content. Plate-
let units may be pathogen-reduced or suspended in
platelet additive solution (two-thirds of the plasma
replaced by saline/nutrient solution) or ‘large-vol-
ume delayed-sampled’ (LVDS; as a way of further
reducing risk of bacterial contamination, 36 h after
the unit is collected, a >8-mL sample is cultured)
&
[14 ]. Pathogen reduction further minimizes risk of
pathogen exposure, and the substitution of additive
solution reduces risk of febrile and allergic reactions
from plasma exposure, viewed as important benefits
in cancer care and other low-volume, repeat-expo-
sure, situations. However, platelet recovery in path-
ogen-reduced units is substantially less (56%) and
the substitution of additive solution for plasma
reduces fibrinogen availability by 0.6 g (18%) [15],
making this product less useful in critical bleeding
situations. The movement of the American Red
Cross, supplier of more than a third of USA blood
products, toward supplying only pathogen-reduced
platelets is a serious concern for the trauma care
community [15].
Despite concerns regarding the administration
of platelets through a rapid infuser device, there is
good evidence that they can be safely given this way
with no loss of efficacy [16].
TRANEXAMIC ACID
Tranexamic acid (TXA) is a lysine analogue used as
an antifibrinolytic. Its use has expanded exponen-
tially in trauma and surgical care since the publica-
tion of the Clinical Randomization of an
Antifibrinolytic in Significant Hemorrhage 2
(CRASH-2) trial in 2010 [17]. This trial, which
recruited more than 20 000 patients worldwide,
showed an all-cause mortality benefit in trauma at
28 days. In CRASH-2, the survival benefit was great-
est in those with signs of hemorrhagic shock (sys-
tolic blood pressure <75mmHg), and subgroup
analysis suggested that administration as soon as
possible after injury, but within 3 h, resulted in the
greatest benefit with increasing concerns regarding
www.co-anesthesiology.com 177
Trauma and transfusion
thrombotic complications after that [18]. No differ-
ences were observed in requirement or volume
of transfusion.
Active debate continues on optimal dosing strat-
egies and timing. Though some pharmacokinetic
evidence on routes of administration has been pub-
&
lished [19 ], dosing remains largely empirical based
on the regimen used in the CRASH-2 trial; a 1 g bolus
dose administered over 10 min, followed by an
intravenous infusion of 1 g over 8 h. Joint Trauma
System and Tactical Combat Casualty Care Guide-
lines recommend it is safe to administer a 2-gram
& &
bolus [20 ,21 ]. The most useful strategies empha-
size the need to tailor use of TXA to specific clinical
situations and patient populations.
CRASH-3 examined the efficacy of TXA use
among patients with traumatic brain injury (TBI)
[22]. This trial demonstrated that TXA reduced TBI
deaths at 28 days when administered within 3 h of
injury. This effect was most pronounced in those
with mild to moderate TBI (GCS 9–15), whereas
patients with the most severe TBI did not appear
to benefit.
FACTOR CONCENTRATES
Normal plasma contains 1 U/mL of each of the
coagulation factors so, when diluted 1 : 4 with cit-
rate anticoagulant, as occurs in normal blood col-
lection, banked plasma contains 0.8 U/mL of each of
the plasma coagulation factors. Seven to 8 units of
80% plasma are required to decrease the interna-
tional normalization ratio (INR) from 2 to 1.4 in a
70 kg adult, making the use of clotting factor con-
centrates a tempting alternative for the rapid treat-
ment of the coagulopathy of trauma, an area of
&
ongoing investigation [23 ].
Currently available concentrates include fibrin-
ogen concentrate, prothrombin complex concen-
trates (PCC) and recombinant factor VIIa.
Concentrates also exist for Factor XI, Factor XIII,
Factor VIII and von Willebrand factor (vWF), and
Factor VIII separately. They are expensive, with
limited supply, and their use is generally restricted
to treatment of the underlying factor deficiencies.
Recombinant factor VIIa failed to show a mor-
tality benefit in randomized clinical trials in both
major trauma [24] and TBI [25]. In these trials, the
drug was given only after informed consent was
obtained from next of kin, perhaps missing a win-
dow where this drug would be most efficacious.
Dutton et al. recognized the pitfalls of conducting
such a trial on a trauma population [26]. A Cochrane
review concluded that the effectiveness of factor VII
as a hemostatic agent, outside hemophilia, remains
unproven [27].
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Four-factor PCC is the treatment of choice for
warfarin reversal, providing high concentrations of
the vitamin K-dependent factors II, VII, IX, and X
and the anticoagulant factors proteins C and S.
However, it is an incomplete treatment for
trauma-induced coagulopathy, lacking fibrinogen,
Factors V, VIII, XI and XIII, vWF, and antiplasmin.
The use of factor concentrates and PCC has
recently been discussed in this journal and we rec-
ommend that review [28].
FIBRINOGEN
No large head-to-head trials of fibrinogen concen-
trate versus cryoprecipitate in trauma yet exist. The
purported advantages of fibrinogen concentrate as a
replacement for cryoprecipitate are its minimum
storage requirements and safety profile, having been
pathogen-reduced and separated from plasma. We
can only look to the Canadian Fibrinogen Replen-
ishment in Surgery (FIBRES) trial for direct compari-
son of these two agents in cardiac surgery [29]. The
outcome of interest in this study was blood compo-
nents administered within 24 h of cardiac by-pass.
The results were that 4 g of fibrinogen concentrate
was not inferior to 10 units of cryoprecipitate (con-
taining 2.86 g of fibrinogen), equivalent in safety,
but at six times the cost. Delays in the availability of
cryoprecipitate are important in critical bleeding
situations but have to do with systems organization
of laboratory and blood bank staffing, not product
efficacy.
Again, a review of this topic was recently pub-
lished in this journal, and we recommend its review
for a summary of the trials of fibrinogen use in
&
trauma [30 ].
BALLOONS AND HEMOSTATIC
DRESSINGS
A variety of devices and materials are available to
reduce exsanguination in patients. Historically,
tourniquets have been used in extremity hemor-
rhage and evidence from recent conflict zones sup-
ports their use in both adults [31] and children
[32,33]. With the advent of the American College
of Surgeons Committee on Trauma ‘Stop the Bleed’
campaign [34] health workers and the lay public are
trained to intervene with basic actions to stop life-
threatening bleeding including deep wound pack-
ing and the use of tourniquets.
Hemorrhage from accessible sites is amenable
both to direct pressure and hemostatic dressings.
Hemostatic dressings range from simple astringents,
immobilizers, or activators to complex active coag-
ulation biologics such as thrombin/fibrinogen
Volume 35  Number 2  April 2022
 Advances in hemorrhage control resuscitation Muldowney et al.
bandages. The wide range in materials, availability,
applicability, and cost merit a review unto
themselves.
For torso hemorrhage at non compressible sites,
Retrograde Endovascular Balloon Occlusion of the
Aorta (REBOA) is a modality to support cardiac and
cerebral perfusion until definitive hemorrhage con-
trol is achieved, both in prehospital and hospital
settings. REBOA has a role in the critically injured,
peri- or in cardiac arrest trauma patient with severe
hemorrhagic shock not responding to blood replace-
ment. Balloon inflation above the renal arteries can
be used in hyper-acute care, but gut and renal ische-
mic injury occur quickly, limiting the length of time
allowable. Gut resuscitation with adenosine, lido-
caine, and magnesium after REBOA is under preclin-
&
ical study [35 ]. Given the circumstances in which it
is used, high-quality prospective trials are difficult to
&
conduct [36 ]. However, a recent 12-month prospec-
tive observational study of patients >15 years old
with immediately life-threatening noncompressible
truncal hemorrhage treated with REBOA at 6 USA
Level 1 trauma centers reports the procedure as
technically safe, with low procedural complication
rates, and associated with successful return of spon-
&
taneous circulation in 59% of patients [37 ].
DESMOPRESSIN
Primary hemostasis starts with the tethering of pla-
telets to exposed subendothelial collagen by vWF.
vWF is made in endothelial cells, stored in their
Weibel-Palade bodies, and secreted in response to
reduced blood flow (decreased surface shear). Secre-
tion can be induced with desmopressin but is subject
to tachyphylaxis.
The first large retrospective cohort study evalu-
ating the use of desmopressin in trauma patients did
&
not find a benefit in neurologic outcome [38 ].
Study patients may have already secreted most of
their vWF in response to their hemodynamic shock,
but the many potential selection biases in this study
design mean that the efficacy of desmopressin
remains unknown. Prospective trials with measures
of vWF are needed.
CALCIUM
Ionized calcium is a critical co-factor for the vitamin
K-dependent clotting factors and required for the
activation of platelets. Outside of the coagulation
system, calcium is also critical for cardiac myocyte
contraction and vascular tone. Every unit of whole
blood contains 9 mM of citrate as an anticoagulant
to permit blood storage. When whole blood, or its
components, are given at 100 mL/min, the ionized
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Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
calcium will decrease to 0.7 mM with a half-time of
2 min and return to normal just as fast when stopped
[39]. Exactly when the rapid and sustained admin-
istration of blood products exceeds the metabolic
capacity of a poorly perfused liver and causes critical
or symptomatic hypocalcemia is not known.
Hypocalcemia is common among all hospital-
ized patients [40], including patients who have suf-
fered trauma. Retrospective studies of clinical data
have shown that the most severely hypocalcemic
patients on presentation required more transfusion
and suffered a higher mortality [41]. Aggressive
treatment of the low ionized calcium seen in most
trauma patients at admission is currently being
advocated as a response to what is being character-
&
ized as the fourth side of a ‘Trauma Diamond’ [42 ].
While there appears to be a correlation between
hypocalcemia, trauma severity, and mortality, cau-
sation has not been shown. There are no prospective
data demonstrating that calcium replacement
&
improves survival. Indeed, Chanthima et al. [43 ]
found no relationship between mortality and first
ionized calcium level, or calcium supplementation
corrected for citrate load.
COAGULATION TESTING SUPPORT IN
HEMOSTATIC RESUSCITATION
As resuscitation strategies evolved to include sup-
port of coagulation capacity, the need for rapid
laboratory testing of platelet and coagulation factor
concentrations and function became obvious and
urgent. This recognition confronted an array of
systems-based barriers to the rapid availability of
laboratory-based coagulation tests. Valid laboratory
testing is based on precision and reproducibility, but
many laboratories are understaffed, and testing is
increasingly outsourced. Bedside viscoelastic testing
emerged to fill this gap. This technology was devel-
oped, marketed, and is now described as a standard
of care despite its failure in large-scale, well-designed
trials to demonstrate improved outcomes in patients
for whom viscoelastic testing was used to guide
&
therapy [44 ,45].
In our hospital, Harborview Medical Center in
Seattle, the laboratory can return an Emergency
Hemorrhage Panel (EHP) of platelet count, hemato-
crit, fibrinogen concentration, and a prothrombin
time/INR within 15 min, at a fraction of the cost of
viscoelastic testing. Repeated use of the EHP at
frequent intervals guides hemotherapy after the
initial acute protocol-based phase of resuscitation
response. We instituted viscoelastic testing for acute
trauma care and removed it when we demonstrated
that it provided no additional useful clinical infor-
mation. Harborview has participated in most of the
www.co-anesthesiology.com 179
Trauma and transfusion
major trials of hemostatic resuscitation with no
decrement in performance and has shared; overall,
the dramatic decrease in hemorrhagic trauma
deaths common to the best trauma care in the era
of hemostatic resuscitation as demonstrated by its
outcome scores in the American College of Surgeons
Trauma Quality Improvement Project.
CONCLUSION
A decade and a half of massive transfusion protocols
drives balanced hemostatic resuscitation to prevent
and treat trauma-induced coagulopathy. However,
basic blood products are changing, and new hem-
orrhage control products and systems are being
introduced. Indeed, even what we consider a mean-
ingful survival metric in prospective trauma trials,
typically 30-day mortality, is changing to reflect the
& 14. Lu W, Delaney M, Dunbar NM, et al. A national survey of hospital-based
early impact of hemorrhage [46 ]. The utility of
drugs to augment hemostasis is an area of major
research, and the need for clinically useful rapid
testing is apparent.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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