Clinical Focus Review Jerrold H. Levy, M.D., F.A.H.A., F.C.C.M.

, Editor

Damage Control Resuscitation in Traumatic Hemorrhage:

It is More Than Fixing the Holes and Filling the Tank
Justin E. Richards, M.D., Deborah M. Stein, M.D., M.P.H., Thomas M. Scalea, M.D.

T rauma remains the leading cause of death and disability

in individuals younger than 44 yr of age, and hemor-
rhage is the most common cause of preventable death after
knowledge gained on the topic of coagulation, and spe-
cifically the cell-based model of hemostasis.11 Therefore,
damage control resuscitation has matured into more than
a traumatic mechanism of injury. Each year nearly 1.5 mil- simply temporary hemorrhage control and intravascu-
lion deaths worldwide are the result of trauma-related hem- lar volume administration. The purpose of this Focused
orrhage.1 During the past 20 yr there has been significant Clinical Review is to address damage control resuscitation
improvement in the management and resuscitation of hem- and the role of the anesthesiologist in the management of
orrhagic shock, attributed in large part to experiences from severe traumatic hemorrhage.
military conflict. First described in the early 1990s, dam-
age control laparotomy reflected such a concept and was
directed toward the timing and method of operative inter-
Early Recognition of Hemorrhage and Massive
vention for abdominal trauma to limit prolonged operations
Transfusion
that occurred with definitive repair, further unnecessary Hemorrhagic shock is a time-dependent disease. In trauma
blood loss, and exposure of an open abdomen to continued patients that survive to hospital admission, the average time
loss of heat and subsequent hypothermia.2,3 Evolution of to death due to hemorrhage is less than 4 h.12,13 Timely
endovascular therapy for certain organ system injuries, such identification of patients at risk for hemorrhage is critical
as splenic, hepatic, and renal trauma, has continued to trans- because delays in resuscitative therapy and administration
form the operative approach to bleeding trauma patients. of blood products are associated with increased mortal-
Successful utilization of endovascular techniques for blunt ity.14 Damage control resuscitation is predicated on early
thoracic aortic injuries is also demonstrated in the trauma blood product transfusion. A widely referenced indicator
surgery literature.4 While these advances have implications and trigger for massive resuscitation is the Assessment of
for minimally invasive management of traumatic injuries, Blood Consumption score, which recognizes a heart rate
the recognition of altered physiology, importance of hemo- more than 120 beats/min, arterial systolic blood pressure
dynamic resuscitation, and correction of coagulopathy are (SBP) less than 90 mmHg, positive Focused Assessment of
critical in patients with active bleeding. Sonography in Trauma examination, and penetrating mech-
After the initial advent of damage control operative anism.15 The presence of two or more of these criteria deter-
techniques to gain rapid control of hemorrhage, dam- mines a positive Assessment of Blood Consumption score
age control resuscitation was described as a concept and reflects a sensitivity and specificity of more than 80% to
that advocated for earlier administration of erythrocytes, identify patients that received a massive transfusion, defined
plasma, and platelets in a ratio that approximated 1:1:1, as more than 10 units of packed red blood cells within 24 h.
in addition to correction of coagulopathy and metabolic This score was comparable to other risk stratification scores.
derangements.2,5 Further observations noted lower rates The advantage of the Assessment of Blood Consumption
of acute respiratory distress syndrome (ARDS)6,7 and score is the relative clinical utility and ease with which it
associations with improved mortality8–10 compared with may be performed immediately at the bedside in the trauma
previous resuscitation strategies that were initiated with bay and does not require delays in waiting for laboratory
crystalloid-based products and later transfusion of blood results, radiographic imaging, or sophisticated computation.
products only when necessary based on laboratory val- The shock index, calculated as the heart rate divided
ues suggesting anemia, coagulopathy, and thrombocyto- by arterial SBP, is an additional marker of injury sever-
penia. During this same period there was considerable ity.16 The utility of the shock index is also evident in

Peter Nagele, M.D., served as Handling Editor for this article.

Submitted for publication April 17, 2023. Accepted for publication July 19, 2023.
Justin E. Richards, M.D.: Department of Anesthesiology, University of Maryland School of Medicine; Program in Trauma, R Adams Cowley Shock Trauma Center, Baltimore, Maryland.
Deborah M. Stein, M.D., M.P.H.: Department of Surgery, University of Maryland School of Medicine; Program in Trauma, R Adams Cowley Shock Trauma Center, Baltimore, Maryland.
Thomas M. Scalea, M.D.: Department of Surgery, University of Maryland School of Medicine; Program in Trauma, R Adams Cowley Shock Trauma Center, Baltimore, Maryland.
Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved. Anesthesiology 2023; XXX:XX–XX. DOI: 10.1097/ALN.0000000000004750

A nesthesiology, V XXX • NO 00 xxx 2023 1

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<zdoi;10.1097/ALN.0000000000004750>
 Clinical Focus Review

the prehospital setting where it easily obtainable and are described in later sections of this review. An appre-
shown to predict the need for blood product transfusion ciation for the mechanism of injury, and that multiple
and lifesaving interventions.17 Similar to the Assessment mechanisms may coexist (such as a gunshot wound in
of Blood Consumption score, the Revised Assessment combination with being struck by a vehicle or assault), is
of Bleeding and Transfusion score includes an admis- integral to the initial physical evaluation and early iden-
sion shock index greater than 1.0 and the presence of tification of hemorrhage.
a pelvic fracture in replacement of heart rate and arte- Clinician “gestalt” is insufficient to expeditiously identify
rial SBP from the Assessment of Blood Consumption patients that should receive massive transfusion. Motameni
score. In multicenter validation, the Revised Assessment et al.21 described that physician decision to initiate mas-
of Bleeding and Transfusion score demonstrated supe- sive transfusion was correct in 73% of patients; however,
rior sensitivity, specificity, and accuracy in identifying more than half of these occurred in the operating room.
patients that received massive transfusion.18 The clini- Furthermore, the authors reported that, if the Assessment
cal application of the shock index is simplified in that of Blood Consumption score had been applied to identify
severely injured patients with a heart rate greater than hemorrhage, the massive transfusion event would have been
the arterial SBP (i.e., shock index more than 1.0) are at initiated in the trauma bay in more than 80% of patients.
increased risk for physiologic derangement and hem- This represents a marked time difference, especially in a
orrhage. There are various scoring systems to identify clinical setting where delays, measured in minutes, in the
patients with acute hemorrhage and an increased risk of delivery of blood products are associated with worse out-
massive transfusion.19 Adoption of these scores is depen- comes.14 The development of massive transfusion protocols
dent on specific institutional capabilities and resources, function such that communication among trauma sur-
and there is no single scoring system that is ideal for geons, anesthesiologists, transfusion medicine, and operating
every institution. figure 1 depicts a flow chart for initial room staff clearly recognize the critical and time-sensitive
damage control resuscitation management. nature of hemorrhagic shock resuscitation.10 The definition
The differences in mechanism of injury are also an of massive transfusion has also evolved over the past two
important point of discussion regarding early recognition of decades with emphasis on damage control resuscitation.
hemorrhage and consequent injury management. A pene- Initially described as more than 10 units of erythrocytes
trating mechanism (caused by gunshot, stab/impalement, or within 24 h, this assumes that severely injured patients sur-
laceration) typically follows a trajectory. In the case of gun- vive long enough to receive the requisite 10 units of eryth-
shot wounds, and even through-and-through stab wounds, rocytes, a concept known as survivor bias. In contemporary
it is critical to account for the number of wounds to align damage control resuscitation practice, there is specific atten-
trajectory and determine anatomic structures (i.e., blood tion to balanced, plasma-based resuscitation in hemorrhagic
vessels, hollow and solid organ structures, osseous structures shock and focused correction of coagulopathy (described
such as the vertebral column) that are at risk for injury. in later sections of this review) with the goal of minimizing
Trajectories that cross multiple body cavities (such as the crystalloid administration and overall blood product trans-
thorax/mediastinum and abdomen) must also be consid- fusion, such that many patients with hemorrhage do not
ered. In addition, the presence of a penetrating mechanism require an excess of 10 units of erythrocytes. For example,
is one of the criteria incorporated into the aforemen- in the seminal Pragmatic, Randomized Optimal Platelet
tioned Assessment of Blood Consumption score to identify and Plasma Ratios (PROPPR) trial, the median total num-
patients at risk for massive transfusion. ber of erythrocytes transfused for each patient was 9 units.13
Patients with a blunt mechanism of injury (i.e., motor The Critical Administration Threshold is described as the
vehicle collisions, motorcycle crashes, pedestrians struck, receipt of more than 3 units of erythrocytes within 1 h and
or falls from greater than standing height) are at risk for is a significant predictor of mortality, superior to that of the
hemorrhage in multiple body cavities that may not be traditional definition of massive transfusion (i.e., more than
easily diagnosed on the body surface. The role of the 10 units within 24 h).22 Trauma patients that are Critical
Focused Assessment of Sonography in Trauma examina- Administration Threshold + within the first hour of hos-
tion in identifying sources of hemorrhage is specifically pital admission are more likely to receive large volumes of
useful in blunt trauma patients with hypotension.20 It is blood products and are at a greater risk of death. Regardless
also worthwhile to note that even falls from a stand- of how massive transfusion is defined, it is critical to recog-
ing height, particularly in patients taking anticoagulation nize that initiation of such an event does not necessitate that
medications, may result in hemorrhage in multiple body patients receive a requisite number of blood products, but
cavities, such as the head, chest (i.e., rib fractures or pul- rather functions to identify injured patients and establish
monary lacerations), abdomen, and/or retroperitoneum communication among multidisciplinary specialists (e.g.,
or pelvis. The goals of resuscitation are impacted by the trauma surgeons, anesthesiologist, transfusion medicine) to
concomitant risk of traumatic brain injury, which may implement time-sensitive resuscitation for severe hemor-
occur in 25% of patients with a blunt mechanism, and rhagic shock.

2 A nesthesiology 2023; XXX:XX–XX Richards et al.

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 Damage Control Resuscitation in Traumatic Hemorrhage

Fig. 1. Indications and algorithm for damage control resuscitation. HR, heart rate; SBP, systolic blood pressure.

Emphasis of Equal Ratio Blood Products, Early trauma patients receiving massive transfusion was associated
Plasma, and Whole Blood in Damage Control with significantly reduced mortality.10,23 The Prospective,
Resuscitation Observational, Multicenter, Major Trauma Transfusion
(PROMMTT) trial reported more that earlier and aggres-
Equal Ratio Resuscitation sive plasma administration was associated with a lower
The contemporary practice of damage control resusci- risk of mortality.9 During the initial 6 h after trauma cen-
tation not only emphasizes timely recognition and trans- ter admission, a critical time point when most patients die
fusion of erythrocytes to patients with hemorrhage, but of hemorrhage, a ratio of FFP:erythrocytes less than 1:2
also early plasma and platelet administration in a ratio that was associated with a more than three-fold increased risk
approximates 1:1:1. Multiple retrospective studies described of death. The association with transfusion ratios and mor-
that earlier fresh frozen plasma (FFP) administration in tality ceased to exist 24 h after admission, highlighting the

Richards et al. A nesthesiology 2023; XXX:XX–XX 3

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 Clinical Focus Review

time-critical nature of hemorrhagic shock resuscitation and lacks oxygen-carrying capacity and contributes to a dilu-
early plasma transfusion. tional coagulopathy. More recently, it has been observed
Similar to plasma, early transfusion of platelets is associated that the administration of crystalloid has a profound effect
with lower risk of death due to hemorrhage after injury.24 on endothelial glycocalyx degradation and dysfunction
Historically, platelet transfusion was reserved for after after hemorrhage.33 An additional contribution from the
administration of crystalloid, erythrocytes, and FFP when PROPPR trial suggests that, in the era of damage con-
conventional laboratory testing revealed thrombocytopenia trol resuscitation with a plasma-based resuscitation, there
(i.e., less than 50,000 platelets). Advancement in coagula- appears to be less crystalloid administration (i.e., approxi-
tion science and viscoelastic hemostatic assays demonstrate mately 6 l within 24 h),13 compared with historical reports
that platelet dysfunction is a common occurrence in acute of 10 l within 24 h.34
traumatic coagulopathy.25 This dysfunction is likely multi-
factorial, but contributed to, in part, by exhaustion of plate- Early Plasma-based Resuscitation
let activation, endothelial damage, hypofibrinogenemia, and
A recent prospective, randomized trial demonstrated a
impaired thrombin generation.25,26 Observational data sug-
survival advantage with early plasma transfusion in blunt
gest that higher ratios of platelets:erythrocytes are associated
trauma patients with severe hemorrhage. The Prehospital
with improved outcomes.24,27,28
Air Medical Plasma (PAMPer) trial reported that patients
There are limited prospective, randomized data that
who received prehospital plasma had a significantly lower
define the amount of erythrocytes, FFP, and platelets or the
30-day mortality compared with patients that received
exact ratio of transfusion in damage control resuscitation.
either packed red blood cells or crystalloid.35 A simulta-
In an attempt to definitively answer the question of supe-
neous trial conducted in an urban environment where
riority of a 1:1:1 transfusion strategy in a prospective, mul-
prehospital plasma transfusion was performed by ground
ticenter trial, the PROPPR study randomly assigned 680
ambulance did not observe similar results.36 There were
patients with a positive Assessment of Blood Consumption
notable differences in the study populations that would
score or physician judgment to receive more than 10 units
explain these disparate findings. A preplanned, post hoc
of erythrocytes within 24 h to either 1:1:1 or 1:1:2 trans-
analysis of data combined from these two trials reported
fusion of platelets, FFP, and erythrocytes, respectively.13 The
that the greatest benefit of early plasma administration
results demonstrated no difference in the primary outcome
was in patients that had a more than a 20-min prehospi-
of 28-day mortality; however, there was a reported decrease
tal transport time and that sustained a blunt mechanism
in the secondary outcomes of 24-h mortality related to
of injury. Considering the goals of damage control resus-
hemorrhage and earlier hemorrhage control in patients
citation, patients also received less crystalloid (approxi-
that received the 1:1:1 transfusion, which should be inter-
mately 5 l) during the initial 24 h,35 even compared with
preted as exploratory in nature. Both groups of patients also
the aforementioned PROPPR trial. The proposed mech-
received higher ratios of plasma than was commonly prac-
anistic advantage of early plasma transfusion in hemor-
ticed in most trauma centers, and the study demonstrated
rhage extends beyond supplementation of clotting factors
the feasibility of a balanced resuscitation strategy. While this
and hyperoncotic solution. A single unit of FFP contains
was considered an overall “negative” trial, the results fur-
approximately 65% of normal clotting factor activity.
ther suggest the importance of early plasma and platelet
Plasma demonstrates a protective and restorative effect on
transfusion.
the endothelial glycocalyx,33 which becomes damaged and
An additional point-of-emphasis in damage control
dysfunctional in the process of shock-induced endotheli-
resuscitation is minimizing crystalloid administration.
opathy.25 Specifically, blunt mechanisms of injury, including
Numerous retrospective studies identified that the volume
traumatic brain injury, may also develop a certain immu-
of crystalloid was significantly associated with ARDS, renal
nologic pathophysiology that benefits from early plasma
failure, delayed abdominal closure, multiple organ failure,
transfusion. Such explanations are hypothesis generating
and mortality.6,7,24,29,30 The maximum volume of crystalloid
in the clinical context of the beneficial effects of plasma
that should be delivered to patients with hemorrhage is
in hemorrhagic shock resuscitation. Nonetheless, the most
undefined; however, previous studies suggest that volumes
recent high-quality data support an early plasma-based
greater than 1.5 to 2 l are associated with greater mortal-
blood product transfusion in traumatic hemorrhage.
ity, and that every 500-ml increment of crystalloid within
the first 6 h of resuscitation is associated with a 9% increase
in risk for ARDS.31 Despite the evolution of damage con-
Whole Blood Resuscitation
trol techniques in the early 1990s, large volumes of crystal- Balanced blood product administration in damage control
loid, in excess of 10 l during the first 24 h, continued to be resuscitation attempts to achieve ratios of erythrocytes,
administered to patients with hemorrhage. The detrimental FFP, and platelets that approximate whole blood. However,
effects of crystalloid resuscitation in hemorrhagic shock are the biologic content of these components does not equate
well-described in the literature,24,29,32 most notably that it to the hemostatic profile that exists in whole blood. For

4 A nesthesiology 2023; XXX:XX–XX Richards et al.

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 Damage Control Resuscitation in Traumatic Hemorrhage

example, when combined in a 1:1:1 ratio of erythrocytes, was clinically obtained. The seminal trial by Bickel et
FFP, and a unit of apheresed platelets, there is a hematocrit al.45 demonstrated that minimal prehospital crystalloid
of approximately 29%, coagulation factor function of 65%, administration resulted in lower mortality in patients
platelet count of 87,000, respectively, and the fibrinogen with penetrating torso trauma. These results have been
content is 850 mg.37 Compared with a single unit of whole misinterpreted to suggest that hypotensive resuscitation
blood that reflects more of a physiologic character, com- reduces mortality, even though arrival arterial SBP was
ponent therapy also introduces more additive solution that not clinically different. A later investigation on prehospi-
lacks oxygen-carrying capacity and may further contrib- tal hypotensive resuscitation suggested that there was an
ute to dilutional coagulopathy. Whole blood resuscitation association with lower mortality in a subgroup of patients
is not a new concept and was the common means of trans- with blunt trauma; even though there was no difference
fusion for hemorrhage during World War I and World War in arterial SBP at hospital arrival between groups, the
II. With advances in transfusion medicine and the ability intervention group received smaller volumes of prehos-
to partition component blood products for specific trans- pital crystalloid.46 These results should be interpreted
fusion indications, whole blood resuscitation became less cautiously and within an appropriate context, especially
common during the mid-twentieth century. Only during considering the detrimental impact of hypotension in
recent military conflict has whole blood re-emerged as a patients with traumatic brain injury. The optimal arterial
potential resuscitative strategy. Low-titer whole blood is systolic and mean arterial blood pressure in patients with
approved for use by the American Association of Blood hemorrhage is not clearly defined and likely dependent
Banks38 and is advocated by the Trauma Hemostasis on patient-specific and injury characteristics (i.e., brain
and Oxygen Research Network39 and the Joint Trauma and spinal cord injury).
Systems Tactical Combat Casualty Care. The advantages of Vasopressor administration to patients with traumatic
whole blood resuscitation are that it involves transfusion hemorrhage has historically been discouraged in North
of a single unit of whole blood that originates from one American trauma systems due to an increased risk of
donor with less risk of immune exposure to exogenous multiple organ failure and mortality. However, the data
antigens when compared with separate components of supporting this practice are limited and based on biased
erythrocytes, FFP, and platelets in a 1:1:1 strategy that are retrospective evidence.47,48 Based on previous work in
derived from multiple donors. There is also less volume hypovolemic patients, there is biologic plausibility that
administered with a single unit of whole blood and is an specific vasopressors are indicated in hemorrhaging
important consideration in damage control resuscitation, trauma patients that remain hypotensive and unresponsive
which aims to minimize excessive volume administration to further blood product administration because these
and the associated risk of transfusion-associated circula- patients are vasodilated.49 Two prospective, randomized
tory overload. Multiple retrospective studies in the civilian trials that evaluated a vasopressin infusion in patients at
environment now demonstrate that cold-stored low-titer risk for massive transfusion observed an overall lower vol-
whole blood is feasible, without any observable increased ume of transfused blood products in patients that received
risk in complications, such as mismatch incompatibility; vasopressin, and no difference in mortality.50,51 It may be
and is associated with decreased mortality.40–43 Two mul- extrapolated that appropriate administration of specific
ticenter, randomized trials are underway in the United vasopressors (i.e., vasopressin) minimizes overall volume
States to investigate whole blood resuscitation for trau- of blood product transfusion and is potentially beneficial.
matic hemorrhage in both the prehospital and in-hospital However, it is important to recognize that these studies
setting. do not define the ideal blood pressure for resuscitation
in hemorrhagic shock or damage control resuscitation.
Hypotensive Resuscitation and Vasopressors in Different recommendations exist regarding blood pres-
Damage Control Resuscitation sure goals in patients with hemorrhage, specifically trau-
matic brain injury, and we refer the reader to statements
In addition to minimal crystalloid administration, certain
from the Trauma Hemostasis and Oxygenation Research
advocates of damage control resuscitation reference hypo-
Network,39 Brain Trauma Foundation Guidelines,52 and
tensive resuscitation as a practice that improves mortal-
European Guideline on Management of Major Bleeding
ity.39 Achieving a lower arterial systolic and mean arterial
and Coagulopathy Following Trauma.53
blood pressure would intuitively reduce bleeding from
uncontrolled sources. A meta-analysis of five randomized
trials stated that hypotensive resuscitation reduces mortal- Acute Traumatic Coagulopathy, Viscoelastic
ity in bleeding trauma patients, even though the quality Hemostatic Assays, and Coagulation
of evidence is low.44 Critical appraisal of the data reveals Supplementation
that the goal of a lower arterial systolic or mean arterial The maturation of damage control resuscitation over the
blood pressure was not achieved in any of these stud- past two decades coincides with advances in the understand-
ies, which questions whether hypotensive resuscitation ing of complex pathophysiologic process of coagulopathy

Richards et al. A nesthesiology 2023; XXX:XX–XX 5

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 Clinical Focus Review

and hemorrhage. The cell-based model of hemostasis has specific coagulation abnormalities with viscoelastic testing
significantly contributed to the science of traumatic coag- would initiate appropriate and timely transfusion of hemo-
ulopathy.11,26 What was initially attributed to excess crystal- static products directed at the specific coagulation deficit. A
loid administration and the absence of expeditious plasma single-center series reported that viscoelastic-guided resus-
transfusion, it is now recognized that acute traumatic coag- citation reduced blood product transfusions and mortality59;
ulopathy is present after injury in 25% of trauma patients.54 however, the Implementing Treatment Algorithms for the
Further compounding the effects of traumatic coagulopathy Correction of Trauma Induced Coagulopathy (iTACTIC)
are hypothermia, acidosis, and hypocalcemia. Hypothermia trial did not observe a difference in mortality or transfu-
is a common occurrence at hospital presentation after trau- sion volumes in the viscoelastic-guided intervention group
matic injury that exacerbates coagulopathy.3,55 Multiple compared with the control group of ratio-based blood
techniques to correct hypothermia are available, including products.60 There were specific limitations to this study
minimizing unnecessary body exposure in the resuscita- that question the overall validity in a population of severely
tion room or operating room, forced-air warming devices, injured and bleeding trauma patients.
increasing ambient room temperature, intravascular warm- Coagulation disorders, such as hypofibrinogenemia and
ing devices, or even extracorporeal support, such as renal clotting factor depletion, are known to occur and con-
replacement therapy and extracorporeal membrane oxy- tribute to traumatic coagulopathy.58,61 Although viscoelas-
genation. Similarly, hypocalcemia is common in patients at tic testing did not demonstrate superiority with regard
risk for massive transfusion and is associated with increased to lower mortality in the iTACTIC trial, a number of
mortality.56 It is unknown if early and aggressive calcium prospective randomized studies have investigated empiric
supplementation results in improved outcomes; however, administration of cryoprecipitate and fibrinogen concen-
vigilant monitoring and maintenance of normal ionized trate in trauma patients at risk of hemorrhage. Results
calcium levels is included in the most recent European suggest that early fibrinogen replacement is feasible and
guidelines on management of severe bleeding. results in greater serum fibrinogen levels and improved
The principals of damage control resuscitation have mit- viscoelastic clotting profiles; however, these studies were
igated the adverse effects of a crystalloid-based resuscitation not designed to demonstrate mortality as a primary out-
and subsequent dilutional coagulopathy while emphasizing come.62–64 Ongoing trials are underway that are expected
aggressive plasma transfusion; however, it is unclear if such to address this question. A recent prospective, randomized
a resuscitation strategy inherently corrects the underlying study from 12 French trauma centers also investigated the
clotting abnormalities present in severely hemorrhaging impact of empiric administration of 4-factor prothrombin
trauma patients. It is reported that platelet dysfunction is complex concentrate (PCC) in patients at risk for massive
a dynamic phenomenon observed in injured patients.25,26 transfusion.65 There was no significant difference in the
Coupled with rapid fibrinogen depletion during massive primary outcome of total 24-h transfusion volume nor
hemorrhage, these processes contribute to a coagulopathy was there an observed difference in mortality at all time
characterized by poor clot strength. This further deterio- points. There were significantly more thrombotic com-
rates with an inability to rapidly generate adequate clotting plications in the PCC treatment group. It is noteworthy
factor activity and thrombin generation, which is necessary that, in these studies, fibrinogen concentrate, cryoprecip-
for the conversion of fibrinogen into a stable foundation of itate, and PCCs were administered empirically and not
fibrin on which platelet binding and hemostatic clotting guided by viscoelastic or conventional laboratory test-
occur.26 Critical hypofibrinogenemia is underrecognized in ing. Therefore, it is plausible that the specific treatment
bleeding patients, likely due to the fact that the threshold was not warranted in a number of participants. It does
for which low fibrinogen is associated with poor outcomes not appear that routine administration of fibrinogen or
is much higher (i.e., less than 150 to 200 mg/dL) than his- PCCs is justified in all patients as a part of damage control
torically taught.57,58 Additionally, the fibrinogen content of resuscitation. Based on available clinical evidence it is also
a single unit of FFP is less than 1 g, and it is unclear if a plas- unclear if viscoelastic-guided resuscitation is superior to
ma-based resuscitation is sufficient to ameliorate the effects ratio-based transfusion.
of hypofibrinogenemia in traumatic hemorrhage.53
More widespread utilization of viscoelastic hemostatic
assays is providing rapid and specific data on clotting abnor- Tranexamic Acid
malities in the context of damage control resuscitation Routine administration of tranexamic acid to trauma
(fig. 1).These assays generate numeric and graphic informa- patients at risk of bleeding gained enthusiasm after the
tion that plot the clotting profile over time, with attention to results of the Clinical Randomization of an Antifibrinolytic
clot initiation, amplification, propagation, and stabilization. in Hemorrhage-2 (CRASH-2) trial that tranexamic acid
Viscoelastic hemostatic assays have demonstrated predictive within 3 h of injury demonstrated a significant reduc-
value in determining the need for massive transfusion and tion in mortality.66 There were numerous methodologic
increased risk of mortality. In theory, identification of the objections, most notably that only half of the enrolled

6 A nesthesiology 2023; XXX:XX–XX Richards et al.

Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved. Unauthorized reproduction of this article is prohibited.
 Damage Control Resuscitation in Traumatic Hemorrhage

patients actually received a blood product transfusion. among the various fibrinolysis phenotypes and association
More recent investigations provide greater insight into the with clinical outcomes.
benefit of early tranexamic acid in patients with traumatic
hemorrhage67,68 (table 1). The Study of Tranexamic Acid
During Air Medical and Ground Prehospital Transport Resolution of Shock and Cessation of Damage
(STAAMP) trial prospectively randomly assigned 927 Control Resuscitation
patients at risk of hemorrhage to prehospital administra- The early initiation of damage control resuscitation with
tion of tranexamic acid versus placebo.68 Although there transfusion of balanced ratios of blood products and the
was no significant difference in mortality, the treatment management of coagulopathy is solidified throughout
effect was similar to the results of CRASH-2, and likely the trauma literature. However, the question of “when
reflects an underpowered sample size. A post hoc analysis of does damage control resuscitation stop?” is not as clearly
the STAAMP trial demonstrated that the greatest observ- defined. A retrospective investigation described specific
able benefit of tranexamic acid occurred in patients with criteria in which cessation of massive transfusion was
hypotension (SBP less than 70 mmHg) and who received appropriate. There is limited evidence to guide massive
tranexamic acid within 1 h of injury,69 and is similar to transfusion termination, and there are multiple clinical
that which was observed in CRASH-2. The optimal dose variables that affect when resuscitation is complete.19
of tranexamic acid is unknown; however, bolus dosing Importantly, massive transfusion termination commu-
of 2 g, with an additional 1 g infusion greater than 8 h, nicates with the blood bank that preparation of large
was safe and effective.68 In damage control resuscitation, quantities of erythrocytes, FFP, platelets, or whole blood
early tranexamic acid administration within 3 h of injury is no longer necessary. After termination of massive trans-
appears beneficial in patients with severe hemorrhage.66–68 fusion events it is likely that patients will continue to
Further controversy on the topic persisted, specifically receive blood products, however, not at the same intensity
regarding the different phenotypes of fibrinolysis (i.e., (e.g., less than 3 units erythrocytes per h). Obvious indi-
fibrinolysis shutdown, physiologic fibrinolysis, and hyper- cations that hemorrhage is controlled include minimal
fibrinolysis).70 Observations with viscoelastic hemostatic visible bleeding in the operative site, or from any other
assays, which includes the later portions of clot forma- sources of injury. Evaluation of volume responsiveness is
tion and analysis of physiologic clot breakdown to prevent a maneuver to determine if further resuscitation results
unnecessary and excessive clot formation (e.g., physiologic in improved cardiovascular function and hemodynamics.
fibrinolysis), suggested that a portion of severely injured End-tidal carbon dioxide (ETco2) is a useful marker to
patients with profound shock (i.e., hypotension, elevated assess improved cardiac output as a result of fluid respon-
lactate) and greater injury severity burden demonstrate siveness. A bolus of 4 ml/kg of intravascular volume that
excessive clot breakdown, known as hyperfibrinolysis. produces an increase in ETco2 ≥ 2 is an accurate pre-
This is proposed to occur through vascular endothelial dictor of volume responsiveness in critically ill patients.72
damage and the generation of tissue plasminogen activa- In the absence of volume responsiveness, an assessment
tor. The effect of tranexamic acid to inhibit the conver- of intrinsic cardiac function is necessary. The utility of
sion of plasminogen to plasmin would seemingly be most transesophageal echocardiography is well-described to
beneficial to those patients with hyperfibrinolysis. On differentiate various etiologies of shock and likely serves
the opposite end of the fibrinolysis spectrum are patients a critical role in damage control resuscitation. However,
with impaired fibrinolysis (e.g., fibrinolysis shutdown), reports of widespread use of intraoperative transesopha-
which is associated with excessive plasminogen activator geal echocardiography in trauma are limited.
inhibitor-1 and represents a majority of trauma patients Hypotension is often the result of vasodilation with
in reported series.70 It was hypothesized that tranexamic severe hemorrhage.49 While vasopressors, such as norepi-
acid administration to patients with fibrinolysis shutdown nephrine or vasopressin, may be indicated, these should be
would result in increased thrombotic complications, mul- used in conjunction with strong clinical decision making so
tiple organ failure, and death.70 However, due to meth- as not to conclude volume resuscitation efforts and overlook
odologic limitations these findings are strictly hypothesis concomitant hypovolemia or depressed cardiac contractility.
generating and have not been confirmed in a prospective, Metabolic and acid-base parameters should improve before
randomized fashion. It is important to recognize that none the cessation of damage control resuscitation, and arterial
of the randomized trials on tranexamic acid have evaluated pH > 7.20 is associated with optimal clot formation.3,5
administration based on viscoelastic test results. Additional There is no high-quality evidence that sodium bicarbon-
data also suggest that fibrinolysis is a complex and tempo- ate administration improves mortality in critically ill trauma
ral phenomenon that evolves over the initial period after patients, and the role of other hydrogen ion buffers is an
severe injury, with certain patients transitioning through area of interest regarding the management of metabolic dis-
different fibrinolysis phenotypes.71 Further work is nec- turbances.73,74 Serum lactate is a valuable marker for injury
essary to determine the interaction of tranexamic acid severity and depth of clinical shock. Observational data

Richards et al. A nesthesiology 2023; XXX:XX–XX 7

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 Clinical Focus Review

Table 1. Prospective, Randomized Trials on Tranexamic Acid in Trauma Patients

Enrolled Primary Primary Out- Notable Secondary Outcome

Trial Inclusion Criteria Intervention Population Outcome come Findings Findings

CRASH-2 Trauma patients 1 g IV tranexamic acid 10,060 28-day mortality Tranexamic acid: Blood product transfusion:
with significant bolus + 1 g infusion 10,067 14.5% tranexamic acid: 50.4%
hemorrhage: SBP at hospital admis- Placebo: Placebo: 51.3% (risk ratio: 0.98,
< 90 mmHg or sion vs. placebo 16% (risk 0.96–1.01, P = 0.21)
HR > 110 ratio: 0.91, Mortality if SBP ≤ 75 mmHg
0.85–0.97, Tranexamic acid: 30.6%
P = 0.0035) Placebo: 35.1% (risk ratio: 0.87,
0.75–0.99)
CRASH-3 Traumatic brain 1 g IV tranexamic acid 4,649 28-day head Tranexamic acid: 28-day head injury–related death in
injury with bolus + 1 g infusion 4,553 injury–related 18.5% mild-moderate traumatic brain injury
Glasgow Coma at hospital admis- death Placebo: tranexamic acid: 5.8%
Scale < 13 or any sion vs. placebo 19.8% (risk Placebo: 7.5% (risk ratio: 0.78,
intracranial bleed ratio: 0.94, 0.64–0.95)
on computed 0.86–1.02) 28-day head injury–related death in
tomography severe head injury
Tranexamic acid: 39.6%
Placebo: 40.1% (risk ratio: 0.99,
0.91–1.07)
Effect of Out-of- Moderate-severe 1 g bolus IV tranexamic 312 6-month Any tranexamic 28-day mortality
Hospital Tranexamic traumatic brain acid prehospital + 345 Glasgow acid: 65% Any tranexamic acid: 14%
Acid vs. Placebo on injury due to blunt 1 g infusion vs. 2 g 309 Outcome Placebo: 62% Placebo: 17% (adjusted difference:
6-Month Functional or penetrating bolus prehospital vs. Scale-Ex- (adjusted –2.9%, –7.9 to 2.1%, P = 0.26)
Neurologic trauma, Glasgow placebo tended > 4 difference: 6-mo disability rating scale (median):
Outcomes in Coma Scale 3–12 –3.5% (–0.9% Tranexamic acid: 1 (0–5)
Patients with and at least 1 to 10.2%, P = Placebo: 1 (0–8) (adjusted difference
Moderate of Severe reactive pupil, 0.84) -0.9%, (–2.5 to 0.7%, P = 0.29)
Trauma Brain Injury SBP < 90 mmHg Progression of Intracranial hemorrhage
Tranexamic acid: 16%
Placebo: 20% (adjusted difference:
–5.4%, –12.8 to 2.1%, P = 0.16)
STAAMP Prehospital trauma 1 g bolus IV tranexamic 151 30-day mortality Any tranexamic 30-day mortality
patients at risk acid prehospital 141 acid: 8.1% Repeat tranexamic acid dose: 7.3%
for hemorrhage vs. 1 gm bolus IV 150 Placebo: 9.9% Placebo: 10% (risk ratio: 0.73,
within 2 h of tranexamic acid 452 (absolute 0.54–0.99)
injury, SBP ≤ 90 prehospital + 1 g difference: 30-day mortality if tranexamic acid
mmHg, HR ≥ 110 bolus at hospital –1.8%, –5.6 < 1 h from injury
arrival vs. 1 g bolus to 1.9%, P = Any tranexamic acid: 4.6%
IV tranexamic acid 0.17) Placebo: 7.6% (risk ratio: 0.6,
prehospital + 1 g 0.44–0.83, P = 0.002)
bolus at hospital
arrival + 1 g infusion
vs. placebo
PATCH Severe trauma 1 g bolus IV tranexamic Tranexamic 6-month Tranexamic acid: 24-h Mortality:
injury, at risk for acid prehospital acid: 657 Glasgow 53.7% Tranexamic acid: 9.7%
trauma-induced + 1 g infusion vs. Placebo: 643 Outcome Placebo: Placebo: 14.1% (risk ratio: 0.69,
coagulopathy placebo Scale- 53.5% (risk 0.51–0.94)
Extended > 4 ratio: 1.00, 28-day mortality:
0.9–1.12; P = Tranexamic acid: 17.3%
0.95) Placebo: 21.8% (risk ratio: 0.79,
0.63–0.99)
6-mo mortality-
tranexamic acid: 19.0%
Placebo: 22.9% (risk ratio: 0.83,
0.67–1.03)
HR, heart rate; SBP, systolic blood pressure.

demonstrate that earlier resolution of lactate is associated resulted in improved mortality. Overall, the conclusion of
with clinical outcomes75,76; however, targeted attempts to damage control resuscitation indicates adequate hemo-
correct an elevated lactate to a specified value, or deter- static control of hemorrhage, intravascular resuscitation, and
mine the optimal threshold for lactate correction, have not improving metabolic parameters.

8 A nesthesiology 2023; XXX:XX–XX Richards et al.

Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved. Unauthorized reproduction of this article is prohibited.
 Damage Control Resuscitation in Traumatic Hemorrhage

Conclusions and Future Directions Research Support

Damage control techniques have evolved during the past Support for this study was provided solely from institutional
20 yr and demonstrate lower rates of morbidity and mor- and/or departmental sources.
tality for traumatically injured patients. Specifically, dam-
age control resuscitation emphasizes rapid identification Competing Interests
of hemorrhage, implementation of massive transfusion Dr. Stein is a consultant for CSL Behring (King of Prussia,
protocols, resuscitation with plasma-based blood products, Pennsylvania) and is the chair of the Data and Safety
correction of coagulopathy, and management of meta- Monitoring Board for the Trauma and Prothrombin
bolic derangements (i.e., acidemia, hypocalcemia, and Complex Concentrate (TAP) Trial. The other authors
hypothermia). There is limited prospective, randomized declare no competing interests.
evidence to definitively prove that specific components
of damage control resuscitation result in superior clinical
Correspondence
outcomes (i.e., 1:1:1 blood product resuscitation, whole
blood transfusion, minimal crystalloid administration, Address correspondence to Dr. Richards: 1200
or early fibrinogen supplementation). However, quality Steuart Street, #319, Baltimore, Maryland 21230.
improvement studies suggest that attention to damage [email protected]. Anesthesiology’s arti-
control resuscitation is associated with increased rates of cles are made freely accessible to all readers on www.
definitive injury repair and improved patient morbid- anesthesiology.org, for personal use only, 6 months from
ity.77 It is important to recognize that modern damage the cover date of the issue.
control resuscitation can exist in the absence of damage
control operative techniques (i.e., abbreviated laparot- References
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Richards et al. A nesthesiology 2023; XXX:XX–XX 13

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