B a l a n c e d R e s u s c i t a t i o n in

Tra u m a M a n a g e m e n t
Paul M. Cantle, MD, MBT, FRCSC, Bryan A. Cotton, MD, MPH, FACS*

KEYWORDS
 Balanced resuscitation  Trauma  Coagulopathy  Hemorrhagic shock
 Damage control

KEY POINTS
 Crystalloid, once considered central to the resuscitation of traumatic hemorrhagic shock,
leads to numerous complications and increases patient morbidity and mortality.
 Trauma-induced coagulopathy is frequent in injured patients at the time of hospital pre-
sentation and is worsened by aggressive crystalloid use.
 Balanced resuscitation minimizes coagulopathy through permissive hypotension, restric-
tive crystalloid use, and high ratios of plasma and platelet to red blood cell transfusion.
 Balanced resuscitation with plasma, platelets, and red blood cells in a 1:1:1 ratio improves
outcomes and should be initiated early, including prehospital, when possible.
 Balanced resuscitation can be achieved through the use of preplanned, matured massive
transfusion protocols, specifically designed to be continued until actively turned off.

INTRODUCTION

As the leading global cause of death among youth and young adults, the impact of
trauma on years of productive life lost cannot be overstated.1 With only brain injury
as a larger cause of overall mortality, hemorrhage is the leading cause of preventable
trauma death.2–6 Rates of mortality in injured patients requiring a massive blood trans-
fusion in the late 1980s were greater than 80%. Prehospital strategies considered
standard of care at the time included early intravenous (IV) access with 2 large-bore
cannulas and aggressive administration of crystalloid, regardless of patient physi-
ology. In the civilian setting, in which blunt trauma predominates, paramedical, emer-
gency, and surgical trauma providers loyally performed these same resuscitation
strategies for several decades. Until recently, they continued to be taught on a global
scale. The Advanced Trauma Life Support Course, used as a benchmark international
trauma reference and teaching tool, and last updated in 2012, still promotes these

Disclosures: Nothing to disclose.

Division of Acute Care Surgery, Department of Surgery, McGovern Medical School, University
Professional Building, Memorial Hermann Hospital, University of Texas, at Houston, 6431 Fan-
nin, MSB 4.286 Houston, TX 77030, USA
* Corresponding author.
E-mail address: [email protected]

Surg Clin N Am 97 (2017) 999–1014

http://dx.doi.org/10.1016/j.suc.2017.06.002 surgical.theclinics.com
0039-6109/17/ª 2017 Elsevier Inc. All rights reserved.
1000 Cantle & Cotton

resuscitation strategies.7,8 As a result, over the last 30 years, the initial resuscitation of
patients with trauma had changed very little. At the start of the new millennium, despite
many significant advances, those patients with significant hemorrhage continued to
have a mortality of more than 50%.9
However, the last decade has witnessed the birth of a new paradigm in early trauma
resuscitation. This radical shift emphasizes balanced resuscitation, using ratios of
plasma, platelets, and red blood cells (RBCs) that approximate whole blood as early
as possible in a patient’s care. It has become understood that aggressive crystalloid
resuscitation worsens coagulopathy through dilution, contributes to acidosis through
pH alteration, and exacerbates hypothermia via infusion of large volumes of cold so-
lution. To address this, a central tenet of balanced resuscitation is to limit early crys-
talloid use in an attempt to attenuate the predictable metabolic derangements that are
associated with this traditional approach. With the addition of permissive hypotension,
the third pillar of balanced resuscitation, current mortalities in hemorrhaging patients
have decreased to as low as 20% (Fig. 1).10 This article focuses on the balanced
resuscitation portion of trauma management. The aim is to understand the motives
behind the long-standing use of crystalloid resuscitation, review the advantages and
disadvantages of various resuscitative agents, and present the compelling evidence
that exists for balanced resuscitation in the management of trauma.

THE HISTORY OF WHOLE-BLOOD AND COMPONENT THERAPY

At the outset of World War 1 (WW1), the British military thought that blood transfusions
caused harm and were instead focused on using crystalloids for resuscitation.11
Concurrently, significant advancements in the tools and techniques necessary for
blood typing, anticoagulation, and storage were being made. As a result, by the end
of WW1, many casualties were being resuscitated with whole blood and this quickly
became the standard of care in several military hospitals. Knowledge of whole
blood–based resuscitation continued to evolve during both World War II (WWII) and
the Korean War. The British had a functional blood transfusion system in place at
the outset of WWII and the United States military shortly followed suit. By the end
of WWII, the American military was mobilizing massive volumes of blood for transfu-
sion. The American Red Cross drew more than 13 million units of whole blood from

Fig. 1. The 3 tenets of balanced resuscitation.

 Balanced Resuscitation in Trauma Management 1001

donors during this war.11 However, product waste was common. For example, during
both the Korean War and the Vietnam War product waste was estimated at greater
than 50%. Although fractionated products, including fresh frozen plasma (FFP),
became available during the Vietnam War, going forward the United States military
focused primarily on the procurement, transport, and storage of large volumes of
RBCs. Despite this, fresh whole blood remained a useful tool because it could be
readily procured from front-line soldiers and avoided the limitation of physical storage
needed for component products. Furthermore, colloids, such as hydroxyethyl starch,
with their significant ability to increase circulating volume and their reduced weight
compared with crystalloids, were being developed and were touted as advantageous
for the transport needs required in the conflict environment.12
In the civilian setting, in which concerns about the volume and weight of fluids used
for resuscitation are minimal, storage of large quantities of product in centralized
blood banks and dedicated care centers is efficient and practical. Whole blood,
depending on the anticoagulant used, can be refrigerated and stored on average for
4 weeks. Using component separation, RBCs can be stored at 2 C to 6 C for 6 weeks
while still maintaining viability, and FFP (plasma that has been frozen within 8 hours of
collection) can be stored at 18 C for 1 year or at 65 C for 7 years.13,14 Plasma sep-
aration from whole blood therefore significantly extends its useful lifespan. Once
thawed, plasma can be kept refrigerated at 1 C to 6 C for a further 5 days while still
retaining useful levels of coagulation factors.15 In the United States, platelets are
stored at room temperature for 5 days, at which point they must be discarded second-
ary to possible bacterial contamination.16 Fractionation also provides the advantage
of targeting components for specific clinical use, including those outside of trauma
and resuscitation, for which individual components rather than whole blood may be
desired (Fig. 2).
Although early work studying transfusion in trauma suggested that component ther-
apy was not necessary to supplement whole blood, once the fractionation of products
occurred, RBCs (and large volumes of crystalloid) alone became the standard to
resuscitate bleeding patients.11,17 The contribution of plasma and platelets to trauma

Fig. 2. The 3 primary components of whole blood.

1002 Cantle & Cotton

resuscitation was discounted and a strategy of crystalloid first then RBCs later took
hold.

THE CRYSTALLOID ADVANTAGE?

Because patients with trauma arrived in the emergency department (ED) without a
type and screen and away from the centralized blood bank, early crystalloid therapy
provided a means to rapidly resuscitate these patients while blood was being pre-
pared.18 With this in mind, crystalloid use in trauma resuscitation had several theoretic
advantages. Most notably, it was seen as an inexpensive resource that was readily
accessible and easily stored. It could be kept in the resuscitation bay or the operating
room in quantities limited only by the physical storage space available. It did not
require a refrigerator and small volumes could be kept in a warmer and readily
replaced. Furthermore, it had an extremely long shelf life, could be mass produced
by industry, rarely required being discarded secondary to expiration, and was cheap
to restock.
Crystalloids were also familiar agents, used on a daily basis by most nurses and
physicians. They required little adaptation for implementation in the resuscitation
bay and did not require monitoring for transfusion reactions. Furthermore, crystalloids
did not require testing for pathogens, such as human immunodeficiency virus (HIV)
and hepatitis, did not pose a risk of blood-borne exposure to either health care
workers or patients, and did not need to be typed or cross-matched. An ongoing crys-
talloid infusion, for the most part, did not require special IV lines or filters. Crystalloids
could also be easily implemented in the prehospital setting, in which the advantages
were similar, including ease of use, storage, and longevity. Patients could arrive at a
resuscitation bay and have the same fluid bag continued while the primary survey
was initiated and while improved IV or central venous access was obtained.
In contrast, blood products cannot be mass produced, require complex collection,
sensitive screening for blood-borne pathogens, and careful means of transport and
storage. They require processing and separation into components and close moni-
toring for transfusion reactions, both early and delayed. To infuse a blood product,
there is a potential delay in order to check the blood band. Their high cost and short
shelf life also mean that their use in the prehospital setting is limited, expensive, and
potentially wasteful. In many countries, there is a history of significant fear of blood
transfusion because of the previous use of tainted products and the infection of
many recipients with hepatitis C and, later, HIV in the 1970s and early 1980s.19,20
This stigma likely further contributed to health care workers’ trepidation with transfu-
sions and probably increased their favor for crystalloids. Blood product use decreased
in trauma care from 54% of patients receiving product in 1991 to 42% in 1995.21 The
overall number of units being transfused between these 2 time points also decreased
significantly.

CRYSTALLOID RESUSCITATION

What was the evidence behind using crystalloid in trauma resuscitation? Clinical expe-
rience with the use of crystalloid in elective and emergency surgical patients expanded
rapidly in the 1980s and 1990s, and many physicians thought that this resuscitation
knowledge was applicable to patients with trauma in hemorrhagic shock. However,
the use of these fluids leads to a decrease in osmotic pressure and an increase in
capillary permeability. A significant portion of the infused volume is lost from the intra-
vascular space into the interstitium. When considering fluid resuscitation in major sur-
gical operations, Shires and colleagues22 showed that, with tissue injury, extracellular
 Balanced Resuscitation in Trauma Management 1003

volume was lost, independent of blood loss. The degree of extracellular volume loss
and internal redistribution seemed to be related to the extent of tissue injury. It was
realized that, despite providing intravascular volume, fluid inherently moved out of
the intravascular and intracellular spaces and into the extracellular space during tissue
trauma, in the form of surgery, and that postoperative extracellular volume was
directly related to the amount of intraoperative fluid administered.23 The focus, there-
fore, became to maintain or even expand the extracellular volume throughout a major
operation, even beyond the fluid volumes that were thought to be necessary for main-
tenance.24 This observation of the contraction of extracellular fluid in surgical patients
suggested that replacement with balanced salt solutions might be of benefit in trauma
resuscitation as well.
Moore and Shires,25 in a 1967 editorial entitled “Moderation,” attempted to stop
these aggressive resuscitation strategies before they became standard practice.
The investigators raised concern about the use of crystalloid solutions to maximize
the intravascular volume and to maintain excess volume in the interstitium so that pa-
tients had the necessary volume to replace any potential losses from bleeding. This
approach was being used to such an extreme that patients were often receiving
more than an entire blood volume equivalent of crystalloid during any major abdominal
surgery. Moore and Shires25 recommended that “replacement during operation
should be carefully estimated and limited” and that blood “should still be replaced dur-
ing major operative surgery as it is lost.” The use of balanced salt solutions, they
added, “appears to be a physiological adjunct to surgical trauma, not a substitute
for blood.” What is often lost, and is critical to remember, is that these cautions
were coming during a time when the blood being used for trauma and major surgery
was whole blood, not simply fractioned components such as RBCs.
Despite this caution, the use of crystalloids for replacement of lost blood gained mo-
mentum. Focus became placed on the prophylactic optimization of defined physio-
logic parameters through intensive, and often invasive, monitoring.26 These invasive
catheters and monitors provided new numbers (cardiac index, pulmonary artery pres-
sures, central venous pressures, and mixed venous oxygen tension) and new labora-
tory values (lactate level, base deficit) to measure. It was no longer considered enough
to simply maintain normal heart rate, blood pressure, and urine output.27 Establishing
and prophylactically maintaining normal patient parameters for each of these criteria in
the critically ill population became the norm, even if extremely aggressive resuscitation
was required to achieve these supraphysiologic results. At this same time, the idea of
the damage-control laparotomy was emerging. This abbreviated laparotomy was
initially described to help manage patients with severe physiologic disturbances by
leaving them open to return for closure once stable.28,29 However, surgeons increas-
ingly found that they struggled to close fascia at subsequent explorations and the
resultant sequelae of abdominal compartment syndrome began to be seen and
treated as a new and accepted entity.30,31
The complications of aggressive crystalloid resuscitation were also being recog-
nized to extend well beyond that of abdominal compartment syndrome. Both normal
saline and lactated Ringer in large volumes have been shown to contribute to various
forms of acidosis. Normal saline leads to a hyperchloremic metabolic acidosis that in
turn leads to decreased cardiac contractility, decreased renal perfusion, and less ion-
otropic response, whereas large volumes of lactated Ringer contribute to a compen-
satory respiratory acidosis.32–34 An overloaded fluid status has been shown to
increase mortality from postoperative pulmonary edema.35 Studies assessing fluid
management strategies in acute lung injury and acute respiratory distress syndrome
have found that a conservative use of fluid leads to more ventilator-free days, shorter
1004 Cantle & Cotton

intensive care unit (ICU) stays, and improved lung function without increasing failure
rates of other organ systems.36 Although, at small doses, fluid may improve cardiac
performance in some populations, aggressive saline resuscitation can further compro-
mise cardiac performance, driving many critically ill surgical patients and patients with
trauma off their optimal Starling curve.37,38 Postoperative patients receiving greater
than 3 L of crystalloid at normal saline concentrations have been shown to have
delayed gastric emptying time, delayed return of bowel function, prolonged hospital
stay, and more perioperative complications compared with a restrictive fluid strat-
egy.39 Overall, it seems that the downsides of crystalloids are extensive, and, despite
their convenience in the trauma bay, they likely do more harm than good in resuscita-
tion for hemorrhagic shock.

COLLOIDS

The advantage of colloids for resuscitation was thought to be that they could signifi-
cantly and rapidly expand circulating volume. Synthetic options including dextran,
starch-based solutions such as hydroxyethyl starch, and plasma-derived albumin all
contain large molecules that exert a significant osmotic effect on the surrounding tis-
sue. They effectively draw fluid into the intravascular space from the interstitial and
intracellular spaces, resulting in both a maintenance and expansion of the circulating
volume in patients with trauma.40,41 Commonly referred to as plasma expanders, as
larger molecule liquids they stay in the intravascular space for a longer period of
time and are able to expand intravascular volume more effectively than crystalloids.
However, in addition to higher cost of colloids, there are several other downsides
compared with crystalloids. There is an uncommon, but recognized, risk of hypersen-
sitivity reaction to these solutions. Dextran is known to reduce platelet aggregation in
some populations and has been used as an anticoagulant in the past.42 Albumin, a
byproduct of human blood fractionation, is expensive to produce. The starch-based
colloid solutions have been associated with anaphylactoid reactions and with renal
failure.43 Importantly, hydroxyethyl starches have been shown to cause coagulop-
athy.44 They reduce maximal clot firmness and reduce all coagulation factor activities,
with the greatest impact on fibrinogen and factor II, XIII, and X activity. They are so
effective at this that they are used to create dilutional coagulopathy in studies evalu-
ating the efficacy of hemostatic adjuncts.45

PLASMA AS THE OPTIMAL RESUSCITATION FLUID

Plasma has long been recognized as an excellent buffer solution.46 It has been shown
to be a 50-fold better buffer than crystalloids and 5-fold better than albumin. This abil-
ity, secondary to its high citrate content, makes it ideal for the resuscitation of patients
in a state of severe acidosis from shock. In addition to containing all necessary clotting
factors and countless microparticles, plasma contains up to 500 mg of fibrinogen per
unit.47 Like colloids, plasma provides the additional benefit of being an excellent vol-
ume expander by leading to a significant increase in osmotic pressure. As a result, it
increases intravascular volume both directly and indirectly by drawing interstitial and
intracellular volume into circulation. Furthermore, plasma has been shown in animal
models to have a positive impact on endothelial vascular integrity by stabilizing the
endothelial glycocalyx and inhibiting permeability by as much as 10-fold.48
So why has its use not been universally adopted? In addition to availability,
transfusion-related events, including ABO incompatibility, transfusion reactions, and
transmission of infections, have been reported. Plasma also has a high cost of pro-
curement, testing, and storage. Opponents of aggressive plasma resuscitation cite
 Balanced Resuscitation in Trauma Management 1005

data that suggest that it leads to a higher incidence of transfusion-related acute lung
injury.49 However, newer, compelling evidence argues that the development of mod-
erate to severe hypoxemia after trauma is more likely to be caused by a patients age,
extent of lung injury, and the use of crystalloid resuscitation and shows no relationship
with product use, whether it be RBCs, plasma, or platelets transfused.50 Animal model
evidence exists that plasma may mitigate the lung injury sustained from shock
compared with crystalloid.51 Acute lung injury after trauma is much more likely to be
caused by hemorrhagic shock and crystalloid resuscitation than by plasma transfu-
sion. Plasma transfusion is likely to be beneficial in this scenario.

THE BALANCED RESUSCITATION STRATEGY

In the setting of hemorrhage, balanced (or damage control) resuscitation refers to the
strategy adopted by the US military to improve outcomes of patients undergoing an
abbreviated laparotomy or other procedure because of grossly disturbed physiology.
As an adjunct to the care of these critically injured patients, its early implementation
focused on delivering higher ratios of plasma and platelets, along with other strategies
to prevent “popping the clot.” Its 3 basic tenets are permissive hypotension, mini-
mizing the use of crystalloid before surgical control of bleeding, and transfusion of
blood products in a ratio approximating whole blood.52 Ideally, this process begins
in the prehospital setting, continues through early trauma bay/emergency room resus-
citation, and is completed in the operating room or the ICU, as needed.
As massive transfusion protocols (MTPs) developed, studies began to explore out-
comes from different product ratios given to patients who ended up requiring more
than 10 units of RBCs within a 24-hour period. Work on determining both the ideal
plasma to RBC and platelet to RBC ratios was pursued. Examining different MTPs
used by different trauma centers and organizations, Malone and colleagues53 sug-
gested that preemptive treatment of coagulopathy with a 1:1:1 product ratio seems
to be associated with improved outcomes and provides the additional benefit of
ease of use. Ho and colleagues54 made a similar argument for this strategy with the
aim of transfusing patients with trauma with factors equivalent to whole blood in a
timely fashion. In 2008, Holcomb and colleagues55 published data from 16 civilian
trauma centers showing that plasma/RBC and platelet/RBC ratios of greater than 1:2
improved early and late survival, primarily through a reduction in rates of truncal hem-
orrhage. They concluded that MTPs should target an ideal ratio of 1:1:1. Gunter and
colleagues56 showed that both higher plasma to RBC and higher platelet to RBC ratios
each individually improved the 30-day mortality of patients with MT trauma. These data
formed the basis for the landmark (The Pragmatic, Randomized Optimal Platelet and
Plasma Ratios trial) PROPPR trial. Investigators directly compared the mortality of pa-
tients with trauma (predicted to receive MT) randomized to a ratio of 1:1:1 versus
1:1:2.10 Although the 2 groups did not have a significant difference in 24-hour or 30-
day mortality, the 1:1:1 group had fewer deaths caused by bleeding and improved rates
of achieving hemostasis. These findings led to the recent Eastern Association for the
Surgery of Trauma’s (EAST) recommendation for transfusion of equal amounts of
RBC, plasma, and platelets during the early, empiric phase of resuscitation.57
The role of fibrinogen (concentrate or cryoprecipitate) in the resuscitation of patients
with hemorrhagic shock remains unclear. Cryoprecipitate acts as a concentrated
source of fibrinogen and other coagulation proteins; however, its transfusion is often
delayed for several hours in patients with trauma. Transfusion of cryoprecipitate within
90 minutes of patient arrival has undergone preliminary study that suggests that it
is feasible to administer and possibly affects mortality.58 As a result, a United
1006 Cantle & Cotton

Kingdom–funded, multicenter, randomized trial comparing early cryoprecipitate trans-

fusion with standard blood transfusion therapy in severely bleeding patients with
trauma is currently underway (CRYOSTAT-2).

PREHOSPITAL RESUSCITATION

In 2011, Haut and colleagues59 showed, in a review of the National Trauma Data Bank,
that patients with trauma who received prehospital IV lines had significantly higher
mortality than those who did not. Given the resuscitation and transfusion trends of
the time period during which these patient data were collected (2001–2005), it is highly
likely that the patients receiving prehospital IV fluid were receiving crystalloid only
resuscitation. They were almost certainly not receiving blood products. In the develop-
ment of guidelines for prehospital fluid administration, EAST found insufficient data to
support the administration of prehospital fluids to severely injured patients as well as
insufficient data to recommend one type of resuscitation fluid rather than another.60 In
2015, a randomized study from the Resuscitation Outcomes Consortium compared a
standard resuscitation protocol of 2 L of fluid plus additional boluses as needed to
maintain a systolic blood pressure of 110 mm Hg or greater against a controlled resus-
citation protocol using 250-mL boluses to maintain a radial pulse or a systolic blood
pressure of 70 mm Hg or greater.61 Simultaneously examining 2 of the tenets of hemo-
static resuscitation (permissive hypotension and limited crystalloid use), the investiga-
tors found that the controlled resuscitation strategy offered an early survival
advantage. In the military setting, this concept had previously been proposed by
both Cannon and colleagues62 and Beecher.63,64 Cannon and colleagues62 in 1918 re-
ported that the “injection of a fluid that will increase blood pressure has dangers in it-
self.” They argued that, in hemorrhage, if the blood pressure is “raised before the
surgeon is ready to check any bleeding that may take place, blood that is sorely
needed may be lost.” Beecher,64 just after WWII, wrote that, before surgical control
of bleeding, “elevation of his systolic blood pressure to about 85 mm Hg is all that
is, necessary. and when profuse internal bleeding is occurring, it is wasteful of
time and blood to attempt to get the patient’s blood pressure up to normal.”
As emphasis has moved away from prehospital crystalloid use, several recent
studies evaluating blood product transfusion (both plasma and RBC) in the prehospital
setting have shown that these products are associated with improved early outcomes,
with little, if any, wastage.65 In addition, patients receiving these products arrive with
improved acid-base status and a lower incidence of coagulopathy.65–67 Several cen-
ters have since developed and matured their protocols with prehospital products
whereby the flight team (nurses and paramedics) may initiate transfusion based on
field variables. Both the Mayo Clinic and University of Texas–Houston initiate plasma
and RBC transfusion based on the prehospital Assessment of Blood Consumption
(ABC) score (Table 1).68,69 Others have recommended the prehospital shock index
to guide blood product use.70

TRAUMA BAY RESUSCITATION

There is increasing evidence that patients should not be aggressively resuscitated

in the prehospital environment and that blood products are of benefit in this setting,
so the question becomes how should clinicians resuscitate these patients once
they arrive at the trauma center, where definitive hemorrhage control can be
attempted and achieved? The data in this setting are more robust, older, and
more convincing than the evolving prehospital literature. As early as 1994, the
concept of a possible benefit from delayed resuscitation was being considered.
 Balanced Resuscitation in Trauma Management 1007

Table 1
Assessment of blood consumption score for the prediction of massive transfusion

Variable Yes or No? (Yes 5 1, No 5 0)

1. Penetrating mechanism Yes/no
2. Positive FAST Yes/no
3. HR  120 bpm Yes/no
4. SBP  90 mm Hg Yes/no
Total out of 4 If 2 5 yes, initiate MTP

Abbreviations: bpm, beats per minute; FAST, focused assessment with sonography for trauma; HR,
heart rate; SBP, systolic blood pressure.

Bickell and colleagues71 reported that patients with penetrating torso injuries who
were randomized to delayed fluid resuscitation (no fluid until operating room arrival)
had improved survival, shorter hospital stays, and fewer complications than those
randomized to immediate crystalloid resuscitation from the scene and during their
ED stays. In 2002, Dutton and colleagues72 reported that the resuscitation of pa-
tients presenting with severe hemorrhage to a systolic pressure of greater than
110 mm Hg was not superior to allowing for permissive hypotension with a systolic
goal of 70 mm Hg. Mortality was similar between these groups, and permissive hy-
potension had the potential to allow better control of bleeding with fewer transfu-
sions than the higher target.
As in the prehospital setting, early recognition of the need for MT is important and
can be facilitated by scores designed for the prediction of MT, such as the ABC
score.68,73 For balanced resuscitation to be effective, blood products, including
plasma and platelets, should be as readily available as RBCs. Ideally, universal thawed
plasma is on hand at the time of patient arrival and, to accomplish this, some centers
have begun stocking their trauma bays/EDs with plasma, which significantly reduces
the time it takes for plasma to be delivered to patients in hemorrhage. Radwan and
colleagues74 showed that having thawed (or liquid) plasma available in the ED was
associated with fewer transfusions of RBC, plasma, and platelets in the first 24 hours
and was an independent predictor of reduced 30-day mortality in this population. The
strategy should therefore be to have thawed AB plasma available in the resuscitation
bay to be used until type-specific plasma can be thawed and becomes available from
the blood bank. However, to have plasma immediately available is challenging in many
centers. If thawed AB plasma in the ED is not feasible or practical, one solution is to
use liquid (never frozen) plasma. Liquid plasma has a hemostatic profile that is supe-
rior to thawed plasma and it can viably be stored in a refrigerated setting for up to
26 days.75 The hemostatic ability of this product, and its long refrigerator storage po-
tential, suggest that it may be the ideal product to be kept within the trauma bay where
it is close at hand for the resuscitation of hemorrhaging patients with trauma. In addi-
tion, although less than 5% of donors are AB blood group, at least 40% of donors are
type A and many of them have low enough titers of anti-B that it can be safely given as
a universal product. Therefore, liquid AB and low-titer A plasma should be strongly
conserved for ED use.

OPERATING ROOM RESUSCITATION

In evaluating all components of damage control resuscitation, including permissive

hypotension, limitation of crystalloids, and delivering high ratios of plasma and
1008 Cantle & Cotton

platelets, Cotton and colleagues76 found that those patients with trauma undergoing
damage control laparotomy had a significant increase in 30-day survival when this
resuscitation strategy was implemented. Morrison and colleagues77 published ran-
domized data that suggested that the hypotensive resuscitation strategy should
potentially extend beyond the trauma bay and into the operating room. They reported
that patients with trauma requiring urgent operative intervention required less fluid and
blood product when an intraoperative MAP target of 50 mm Hg was used, as opposed
to an MAP target of 65 mm Hg, but these patients also had lower rates of early post-
operative mortality and a trend toward lower overall mortality. They were also less
likely to develop early coagulopathy, less likely to have a severe coagulopathy, and
less likely to die from bleeding. The investigators concluded that a hypotensive resus-
citation strategy is safe in trauma. Duke and colleagues78 showed that, as part of a
damage control resuscitation strategy, restrictive fluid use in patients with trauma,
compared with standard fluid use, led to lower rates of intraoperative mortality and
shorter lengths of hospital stay. In addition, the PROPPR trial noted that, compared
with patients receiving 1:1:2 ratio, those receiving a 1:1:1 ratio more rapidly achieved
clinical hemostasis, had their MTP discontinued sooner, and had lower bleeding-
related mortality.10 Continuing a balanced resuscitation strategy intraoperatively is
critical.
One of the intrinsic benefits of an MTP is to provide the resuscitation team with the
ability to transfuse patients without having to track product ratios closely during an
intense operation and resuscitation. Each MTP pack should be designed to contain
a balanced ratio of product and each patient should receive 1 complete pack before
moving onto the next. This system compels the resuscitation team to provide a
balanced ratio of product, rather than transfusing based on delayed laboratory re-
sults or personal sentiment. In addition to ensuring that patients receive hemostatic
ratios, this strategy removes a responsibility from the numerous demands already
placed on resuscitation teams as they multitask through the resuscitations, providing
a secondary benefit to patients by allowing the teams to focus instead on other
important tasks.

INTENSIVE CARE UNIT RESUSCITATION

In general, hemorrhage sufficient to warrant an MT requires ICU admission. Arrival of

these patients to the ICU marks an important checkpoint or node in the patient’s care
and should prompt a review of the resuscitative efforts so far and a plan and direction
for further care. In addition to addressing factors that exacerbate coagulopathy,
including hypothermia, acidosis, and hypocalcemia, clinicians should ask whether
the patient is still receiving MTP or whether the patient has been transitioned to
laboratory-directed resuscitation. An appropriate laboratory-directed algorithm
should be in place, and care at this point should be guided according to these assays.
If an active MTP is still required, clinicians should ask whether the patient warrants a
return to the operating room. If not, blood pressures targets may be returned to normal
and supportive or maintenance fluids begun. However, should the patient’s abdomen
remain open, substituting hypertonic saline for maintenance fluids (rather than stan-
dard crystalloids) should be considered to reduce bowel wall and mesenteric
edema.79
With respect to continued high ratios of plasma and platelets, the PROMMTT
(Prospective, Observational, Multicenter, Major Trauma Transfusion) study provided
answers to this question.80 This prospective cohort study found that higher (1:1:1)
ratios of plasma and platelet to RBC decreased patient mortality during the first
 Balanced Resuscitation in Trauma Management 1009

6 hours. However, the investigators noted that, after 6 hours (and continuing through
30 days), although higher ratios were not associated with increased complications
they were also of no benefit.

RETURN TO WHOLE BLOOD

The reasons for a shift away from whole-blood transfusion were many. With ad-
vances in blood banking, fractionation provided a means by which components spe-
cific to the needs of the patient, including patients without trauma, could be provided
without having to administer whole blood. Furthermore, blood banking provided a
means by which some components could be stored for extended durations, thereby
decreasing concerns about a limited and time-sensitive supply. As a result, whole
blood was removed as an available product. However, this was done without consid-
eration of whether whole blood was more or less superior to component therapy in
the resuscitation of hemorrhaging patients. In 2013, Cotton and colleagues81 chal-
lenged the assumption that component therapy was equal to whole blood by
completing a pilot randomized controlled trial. They discovered that the use of modi-
fied whole blood did not decrease transfusion volumes compared with component
therapy. However, when patients with severe brain injuries were excluded, the
remaining patients receiving modified whole blood required less volume of transfu-
sion than those receiving component therapy. Of note, the modified whole-blood
group required the additional transfusion of platelets at a ratio equivalent to the
component therapy group. This work suggests that the use of whole blood may
lead to similar survival outcomes as component therapy but with a decrease in the
volume of transfusion required to achieve this goal. Further work by the Early Whole
Blood Investigators has found that patients transfused with modified whole blood
compared with component therapy showed improved thrombin potential and platelet
aggregation.82 This area requires further study. The use of fresh whole blood is likely
to continue in the military setting because it has been found to be convenient, safe,
and effective.83

SUMMARY

Balanced resuscitation has become a key tenet in the care of patients with
trauma. The implementation of this central strategy has been associated with
reduced death from major bleeding, decreasing reported mortalities from
more than 60% in 2007 to as low as 20% currently. During this time, clinicians
have begun to appreciate that aggressive crystalloid resuscitation leads to signifi-
cant clinical complications and harm and that massive fluid resuscitation should
be avoided. The use of crystalloids and colloids should be as thoughtful and careful
as with any medication. When the limitation of crystalloid resuscitation is combined
with permissive hypotension, prevention of hypothermia, and the transfusion of
component blood into ratios that match the composition of whole blood early in
the care of patients with trauma, outcomes are significantly improved. Balanced
resuscitation provides an early means to treat trauma-induced coagulopathy,
leads to an overall decrease in the use of blood products, and improves patient
survival. Although further advances in the resuscitation strategies used to
treat patients with trauma will be made and improvements in patient-specific
targeting of transfusions will be developed, there is little doubt that balanced resus-
citation using modern MTPs is likely here to stay. Bleeding needs blood to stop
bleeding.
1010 Cantle & Cotton

REFERENCES

1. Cothren CC, Moore EE, Hedegaard HB, et al. Epidemiology of urban trauma
deaths: a comprehensive reassessment 10 years later. World J Surg 2007;
31(7):1507–11.
2. Centers for Disease Control and Prevention. Web-based injury statistics query
and reporting system. Atlanta (GA): US Department of Health and Human Ser-
vices, CDC, National Center for Injury Prevention and Control; 2003.
3. Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: a reassess-
ment. J Trauma 1995;38(2):185–93.
4. Acosta JA, Yang JC, Winchell RJ, et al. Lethal injuries and time to death in a level I
trauma center. J Am Coll Surg 1998;186(5):528–33.
5. Rhee P, Joseph B, Pandit V, et al. Increasing trauma deaths in the United States.
Ann Surg 2014;260(1):13–21.
6. Tieu BH, Holcomb JB, Schreiber MA. Coagulopathy: its pathophysiology and
treatment in the injured patient. World J Surg 2007;31(5):1055–64.
7. American College of Surgeons Committee on Trauma. ATLS, advanced trauma
life support student course manual. 9th edition. Chicago: American College of
Surgeons; 2012.
8. ATLS Subcommittee, American College of Surgeons’ Committee on Trauma, In-
ternational ATLS Working Group. Advanced trauma life support (ATLS): the
ninth edition. J Trauma 2013;74(5):1363–6.
9. Cinat ME, Wallace WC, Nastanski F, et al. Improved survival following massive
transfusion in patients who have undergone trauma. Arch Surg 1999;134(9):
964–8.
10. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red
blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma:
the PROPPR randomized clinical trial. JAMA 2015;313(5):471–82.
11. Hess JR, Thomas MJ. Blood use in war and disaster: lessons from the past cen-
tury. Transfusion 2003;43(11):1622–33.
12. Holcomb JB. Fluid resuscitation in modern combat casualty care: lessons
learned from Somalia. J Trauma 2003;54(5S):S46–51.
13. Sullivan MT, Cotten R, Read EJ, et al. Blood collection and transfusion in the
United States in 2001. Transfusion 2007;47(3):385–94.
14. Dumont LJ, AuBuchon JP. Evaluation of proposed FDA criteria for the evaluation
of radiolabeled red cell recovery trials. Transfusion 2008;48(6):1053–60.
15. Downes KA, Wilson E, Yomtovian R, et al. Serial measurement of clotting factors
in thawed plasma stored for 5 days. Transfusion 2001;41(4):570.
16. Hess JR. Conventional blood banking and blood component storage regulation:
opportunities for improvement. Blood Transfus 2010;8(S3):S9–15.
17. Counts RB, Haisch C, Simon TL, et al. Hemostasis in massively transfused trauma
patients. Ann Surg 1979;190(1):91–9.
18. Carrico CJ, Canizaro PC, Shires GT. Fluid resuscitation following injury: rationale
for the use of balanced salt solutions. Crit Care Med 1976;4(2):46–54.
19. Picard A. The gift of death: confronting Canada’s tainted-blood tragedy. Toronto:
HarperCollins; 1995.
20. Meier, B. Blood, money and aids: haemophiliacs are split; liability cases bogged
down in disputes. The New York Times. June 11, 1996.
21. Farion KJ, McLellan BA, Boulanger BR, et al. Changes in red cell transfusion
practice among adult trauma victims. J Trauma 1998;44(4):583–7.
 Balanced Resuscitation in Trauma Management 1011

22. Shires T, Williams J, Brown F. Acute change in extracellular fluids associated with
major surgical procedures. Ann Surg 1961;154(5):803–10.
23. Virtue RW, LeVine DS, Aikawa JK. Fluid shifts during the surgical period: RISA
and s35 determinations following glucose, saline or lactate infusion. Ann Surg
1966;163(4):523–8.
24. Nielsen OM, Engell HC. The importance of plasma colloid osmotic pressure for
interstitial fluid volume and fluid balance after elective abdominal vascular sur-
gery. Ann Surg 1986;203(1):25–9.
25. Moore FD, Shires GT. Moderation. Ann Surg 1967;166(2):300–1.
26. Shoemaker WC, Appel P, Bland R. Use of physiologic monitoring to predict
outcome and to assist in clinical decisions in critically ill postoperative patients.
Am J Surg 1983;146(1):43–50.
27. Abramson D, Scalea TM, Hitchcock R, et al. Lactate clearance and survival
following injury. J Trauma 1993;35(4):584–8.
28. Stone HH, Strom PR, Mullins RJ. Management of the major coagulopathy with
onset during laparotomy. Ann Surg 1983;197(5):532–5.
29. Rotondo MF, Schwab CW, McGonigal MD, et al. ‘Damage control’: an approach
for improved survival in exsanguinating penetrating abdominal injury. J Trauma
1993;35(3):375–82.
30. Fietsam R Jr, Villalba M, Glover JL, et al. Intra-abdominal compartment syndrome
as a complication of ruptured abdominal aortic aneurysm repair. Am Surg 1989;
55(6):396–402.
31. Bendahan J, Coetzee CJ, Papagianopoulos C, et al. Abdominal compartment
syndrome. J Trauma 1995;38(1):152–3.
32. Scheingraber S, Rehm M, Sehmisch C, et al. Rapid saline infusion produces hy-
perchloremic acidosis in patients undergoing gynecologic surgery. Anesthesi-
ology 1999;90(5):1265–70.
33. Williams EL, Hildebrand KL, McCormick SA, et al. The effect of intravenous
lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmo-
lality in human volunteers. Anesth Analg 1999;88(5):999–1003.
34. Takil A, Eti Z, Irmak P, et al. Early postoperative respiratory acidosis after large
intravascular volume infusion of lactated ringer’s solution during major spine sur-
gery. Anesth Analg 2002;95(2):294–8.
35. Arieff AI. Fatal postoperative pulmonary edema: pathogenesis and literature re-
view. Chest 1999;115(5):1371–7.
36. Wiedemann HP, Wheeler AP, Bernard GR, et al, National Heart, Lung, and Blood
Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.
Comparison of two fluid-management strategies in acute lung injury. N Engl J
Med 2006;354(24):2564–75.
37. Richard C, Warszawski J, Anguel N, et al, French Pulmonary Artery Catheter
Study Group. Early use of the pulmonary artery catheter and outcomes in patients
with shock and acute respiratory distress syndrome: a randomized controlled
trial. JAMA 2003;290(20):2713–20.
38. Sandham JD, Hull RD, Brant RF, et al, Canadian Critical Care Clinical Trials
Group. A randomized, controlled trial of the use of pulmonary-artery catheters
in high-risk surgical patients. N Engl J Med 2003;348(1):5–14.
39. Lobo DN, Bostock KA, Neal KR, et al. Effect of salt and water balance on recov-
ery of gastrointestinal function after elective colonic resection: a randomised
controlled trial. Lancet 2002;359(9320):1812–8.
40. Lamke LO, Liljedahl SO. Plasma volume expansion after infusion of 5%, 20% and
25% albumin solutions in patients. Resuscitation 1976;5(2):85–92.
1012 Cantle & Cotton

41. Tønnessen T, Tølløfsrud S, Kongsgaard UE, et al. Colloid osmotic pressure of

plasma replacement fluids. Acta Anaesthesiol Scand 1993;37(4):424–6.
42. Robless P, Okonko D, Mikhailidis DP, et al. Dextran 40 reduces in vitro platelet ag-
gregation in peripheral arterial disease. Platelets 2004;15(4):215–22.
43. Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hydroxyethyl
starch administration with mortality and acute kidney injury in critically ill patients
requiring volume resuscitation: a systematic review and meta-analysis. JAMA
2013;309(7):678–88.
44. Fenger-Eriksen C, Tønnesen E, Ingerslev J, et al. Mechanisms of hydroxyethyl
starch-induced dilutional coagulopathy. J Thromb Haemost 2009;7(7):1099–105.
45. Schramko AA, Suojaranta-Ylinen RT, Kuitunen AH, et al. Rapidly degradable
hydroxyethyl starch solutions impair blood coagulation after cardiac surgery: a
prospective randomized trial. Anesth Analg 2009;108(1):30–6.
46. Traverso LW, Medina F, Bolin RB. The buffering capacity of crystalloid and colloid
resuscitation solutions. Resuscitation 1985;12(4):265–70.
47. Ketchum L, Hess JR, Hiippala S. Indications for early fresh frozen plasma, cryo-
precipitate, and platelet transfusion in trauma. J Trauma 2006;60(6S):S51–8.
48. Pati S, Matijevic N, Doursout MF, et al. Protective effects of fresh frozen plasma on
vascular endothelial permeability, coagulation, and resuscitation after hemor-
rhagic shock are time dependent and diminish between days 0 and 5 after
thaw. J Trauma 2010;69(S1):S55–63.
49. Khan H, Belsher J, Yilmaz M, et al. Fresh-frozen plasma and platelet transfusions
are associated with development of acute lung injury in critically ill medical pa-
tients. Chest 2007;131(5):1308–14.
50. Robinson BR, Cotton BA, Pritts TA, et al. Application of the Berlin definition in
PROMMTT patients: the impact of resuscitation on the incidence of hypoxemia.
J Trauma 2013;75(1S):S61–7.
51. Kozar RA, Peng Z, Zhang R, et al. Plasma restoration of endothelial glycocalyx in
a rodent model of hemorrhagic shock. Anesth Analg 2011;112(6):1289–95.
52. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly ad-
dressing the early coagulopathy of trauma. J Trauma 2007;62(2):307–10.
53. Malone DL, Hess JR, Fingerhut A. Massive transfusion practices around the
globe and a suggestion for a common massive transfusion protocol. J Trauma
2006;60(6 Suppl):S91–6.
54. Ho AM, Karmakar MK, Dion PW. Are we giving enough coagulation factors during
major trauma resuscitation? Am J Surg 2005;190(3):479–84.
55. Holcomb JB, Wade CE, Michalek JE, et al. Increased plasma and platelet to red
blood cell ratios improves outcome in 466 massively transfused civilian trauma
patients. Ann Surg 2008;248(3):447–58.
56. Gunter OL Jr, Au BK, Isbell JM, et al. Optimizing outcomes in damage control
resuscitation: identifying blood product ratios associated with improved survival.
J Trauma 2008;65(3):527–34.
57. Cannon JW, Khan MA, Raja AS, et al. Damage control resuscitation in patients
with severe traumatic hemorrhage: a practice management guideline from the
Eastern Association for the Surgery of Trauma. J Trauma 2017;82(3):605–17.
58. Curry N, Rourke C, Davenport R, et al. Early cryoprecipitate for major haemor-
rhage in trauma: a randomised controlled feasibility trial. Br J Anaesth 2015;
115(1):76–83.
59. Haut ER, Kalish BT, Cotton BA, et al. Prehospital intravenous fluid administration
is associated with higher mortality in trauma patients: a National Trauma Data
Bank analysis. Ann Surg 2011;253(2):371–7.
 Balanced Resuscitation in Trauma Management 1013

60. Cotton BA, Jerome R, Collier BR, et al, Eastern Association for the Surgery of
Trauma Practice Parameter Workgroup for Prehospital Fluid Resuscitation.
Guidelines for prehospital fluid resuscitation in the injured patient. J Trauma
2009;67(2):389–402.
61. Schreiber MA, Meier EN, Tisherman SA, et al, ROC Investigators. A controlled
resuscitation strategy is feasible and safe in hypotensive trauma patients: results
of a prospective randomized pilot trial. J Trauma 2015;78(4):687–95.
62. Cannon WB, Fraser J, Cowell EM. The preventive treatment of wound shock.
JAMA 1918;70:618–21.
63. Beecher HK. Preparation of battle casualties for surgery. Ann Surg 1945;21:
769–92.
64. Beecher HK. Resuscitation and anesthesia for wounded men. Springfield (IL):
Banerstone House; 1949.
65. Holcomb JB, Donathan DP, Cotton BA, et al. Prehospital transfusion of plasma
and red blood cells in trauma patients. Prehosp Emerg Care 2015;19(1):1–9.
66. Kim BD, Zielinski MD, Jenkins DH, et al. The effects of prehospital plasma on pa-
tients with injury: a prehospital plasma resuscitation. J Trauma 2012;73(2 Suppl
1):S49–53.
67. Brown JB, Sperry JL, Fombona A, et al. Pre-trauma center red blood cell trans-
fusion is associated with improved early outcomes in air medical trauma patients.
J Am Coll Surg 2015;220(5):797–808.
68. Nunez TC, Voskresensky IV, Dossett LA, et al. Early prediction of massive trans-
fusion in trauma: simple as ABC (assessment of blood consumption)? J Trauma
2009;66(2):346–52.
69. Goodman MD, Hawes HG, Pommerening MJ, et al. Prehospital ABC score accu-
rately triages patients who will require immediate resource utilization. Presented
at the 72nd Annual Meeting of AAST and Clinical Congress of Acute Care Sur-
gery. San Francisco, CA, September 18–21, 2013.
70. Parimi N, Hu PF, Mackenzie CF, et al. Automated continuous vital signs predict
use of uncrossed matched blood and massive transfusion following trauma.
J Trauma 2016;80(6):897–906.
71. Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versus delayed fluid resuscita-
tion for hypotensive patients with penetrating torso injuries. N Engl J Med 1994;
331(17):1105–9.
72. Dutton RP, Mackenzie CF, Scalea TM. Hypotensive resuscitation during active
hemorrhage: impact on in-hospital mortality. J Trauma 2002;52(6):1141–6.
73. Cantle PM, Cotton BA. Prediction of massive transfusion in trauma. Crit Care Clin
2017;33(1):71–84.
74. Radwan ZA, Bai Y, Matijevic N, et al. An emergency department thawed plasma
protocol for severely injured patients. JAMA Surg 2013;148(2):170–5.
75. Matijevic N, Wang YW, Cotton BA, et al. Better hemostatic profiles of never-frozen
liquid plasma compared with thawed fresh frozen plasma. J Trauma 2013;74(1):
84–90.
76. Cotton BA, Reddy N, Hatch QM, et al. Damage control resuscitation is associated
with a reduction in resuscitation volumes and improvement in survival in 390 dam-
age control laparotomy patients. Ann Surg 2011;254(4):598–605.
77. Morrison CA, Carrick MM, Norman MA, et al. Hypotensive resuscitation strategy
reduces transfusion requirements and severe postoperative coagulopathy in
trauma patients with hemorrhagic shock: preliminary results of a randomized
controlled trial. J Trauma 2011;70(3):652–63.
1014 Cantle & Cotton

78. Duke MD, Guidry C, Guice J, et al. Restrictive fluid resuscitation in combination
with damage control resuscitation: time for adaptation. J Trauma 2012;73(3):
674–8.
79. Harvin JA, Mims MM, Duchesne JC, et al. Chasing 100%: the use of hypertonic
saline to improve early, primary fascial closure after damage control laparotomy.
J Trauma 2013;74(2):426–30.
80. Holcomb JB, del Junco DJ, Fox EE, et al, PROMMTT Study Group. The Prospec-
tive, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study:
comparative effectiveness of a time-varying treatment with competing risks.
JAMA Surg 2013;148(2):127–36.
81. Cotton BA, Podbielski J, Camp E, et al, Early Whole Blood Investigators.
A randomized controlled pilot trial of modified whole blood versus component
therapy in severely injured patients requiring large volume transfusions. Ann
Surg 2013;258(4):527–32.
82. Rahbar E, Cardenas JC, Matijevic N, et al, Early Whole Blood Investigators.
Trauma, time, and transfusions: a longitudinal analysis of coagulation markers
in severely injured trauma patients receiving modified whole blood or component
blood products. Shock 2015;44(5):417–25.
83. Kauvar DS, Holcomb JB, Norris GC, et al. Fresh whole blood transfusion: a
controversial military practice. J Trauma 2006;61(1):181–4.