Review

Clinical and cellular effects of hypothermia, acidosis

and coagulopathy in major injury
K. Thorsen1 , K. G. Ringdal3,4 , K. Strand2 , E. Sreide2,5 , J. Hagemo3 and K. Sreide1,5
Departments of 1 Surgery and 2 Anaesthesiology and Intensive Care, Stavanger University Hospital, Stavanger, 3 Department of Research, Norwegian Air
Ambulance Foundation, Drbak, 4 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, and 5 Department of Surgical Sciences,
University of Bergen, Bergen, Norway
Correspondence to: Associate Professor K. Sreide, Department of Surgery, Stavanger University Hospital, PO Box 8100, N-4068 Stavanger, Norway
(e-mail: ksoreide@mac.com)

Background: Hypothermia, acidosis and coagulopathy have long been considered critical combinations

after severe injury. The aim of this review was to give a clinical update on this triad in severely injured
patients.
Methods: A non-systematic literature search on hypothermia, acidosis and coagulopathy after major
injury was undertaken, with a focus on clinical data from the past 5 years.
Results: Hypothermia (less than 35 C) is reported in 16133 per cent of injured patients. The
occurrence of acidosis is difficult to estimate, but usually follows other physiological disturbances.
Trauma-induced coagulopathy (TIC) has both endogenous and exogenous components. Endogenous
acute traumatic coagulopathy is associated with shock and hypoperfusion. Exogenous effects of dilution
from fluid resuscitation and consumption through bleeding and loss of coagulation factors further
add to TIC. TIC is present in 1034 per cent of injured patients, depending on injury severity,
acidosis, hypothermia and hypoperfusion. More expedient detection of coagulopathy is needed.
Thromboelastography may be a useful point-of-care measurement. Management of TIC is controversial,
with conflicting reports on blood component therapy in terms of both outcome and ratios of blood
products to other fluids, particularly in the context of civilian trauma.
Conclusion: The triad of hypothermia, acidosis and coagulopathy after severe trauma appears to be
fairly rare but does carry a poor prognosis. Future research should define modes of early detection and
targeted therapy.
Paper accepted 10 February 2011
Published online 20 April 2011 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.7497

Introduction

Injury is a leading cause of death and disability worldwide, particularly in young people1 . A main cause of
death in the rst hours after trauma is bleeding. Up
to 25 per cent of all fatalities of trauma are caused by
uncontrolled haemorrhage2 6 . Unrecognized hypoperfusion from bleeding injuries has consequences for the subsequent development of respiratory and multiorgan failure.
The objective assessment of pending or established
hypovolaemic shock is difcult. Hypotension does not
always mean hypovolaemia and hypoperfusion of tissues.
For example, hypotension as a consequence of general
anaesthesia or spinal cord injury is not associated with
hypoperfusion. Hypotension as a predictor of hypo 2011 British Journal of Surgery Society Ltd
Published by John Wiley & Sons Ltd

perfusion is believed to start at a higher systolic blood

pressure (SBP) of 110 mmHg7 than the limit of less
than 90 mmHg often used to dene shock8 . Less than
half of all shocked patients are identied using SBP as
the sole determinant of hypoperfusion, and associated
traumatic brain injury further hampers the use of SBP as
a determinant of major haemorrhage or hypoperfusion9 .
Changes in vital signs with volume loss used by the
TM
Advanced Trauma Life Support (ATLS ), such as
stages I to IV for shock, have been challenged for their
clinical relevance8 . SBP, pulse and respiratory rate have
been investigated in large cohorts of patients10 , with
ndings indicating that real life does not mirror textbook descriptions of shock. SBP is notoriously difcult
British Journal of Surgery 2011; 98: 894907

Hypothermia, acidosis and coagulopathy in major injury

to monitor and reproduce by non-invasive standards.

Automated measurements often overestimate the actual
blood pressure for those with true hypotension (as
assessed by manual measurements)11 . Recognizing the
dynamic situation of trauma resuscitation, even a single
drop in SBP is found to be detrimental in otherwise
stable patients, with associated increases in morbidity
and mortality12 .
Uncontrolled bleeding injuries are thought to induce
a lethal triad of trauma. This triad, consisting of
hypothermia, acidosis and coagulopathy, is a detrimental
prognostic factor for the traumatized patient. The
implementation of damage control principles, during
resuscitation and surgery, has enabled better control
of these effects of trauma previously associated with
high mortality rates13 16 . A newer and more complex
understanding of the mechanisms of hypothermia, acidosis
and coagulopathy, however, has evolved in recent years
(Fig. 1). This review provides an update of the current
clinical understanding of hypothermia, acidosis and
coagulopathy related to major trauma.
Methods

A PubMed/MEDLINE, Web of Science and Embase

search was made using the search words hypothermia,

Major
trauma
insult

895

acidosis, coagulopathy, exsanguination, bleeding and

lethal triad combined with trauma and injury. The
study was planned by the rst and last authors, who
performed the initial literature search and manuscript
draft. Further search, content revision and discussion until
agreement were performed by all authors. All authors
searched both electronically and in bibliographies of
retrieved articles to identify further studies of interest.
Articles or studies published over the past 5 years (January
2005 and December 2010 inclusive) with a clinical focus
relating to civilian trauma were given priority for inclusion.
Data from military experience or experimental studies
were included where data from civilian trauma were
lacking.
Hypothermia

Post-traumatic hypothermia is either spontaneous when

caused by the accident or insult per se (such as exposure or
bleeding), or therapeutic. Distinguishing between the two
types of hypothermia is important because of the different
mechanisms and effects involved. Clinical experience
from cardiac arrest survivors has revealed substantially
better outcomes in patients with therapeutically induced
hypothermia compared with those who have spontaneous
(accidental) hypothermia after resuscitation17 .

Bleeding
Tissue injury

Hypoxia
Hypotension

Loss of
blood

Shock

Acidosis
Resuscitation
Hypothermia

Hypovolaemia
Endogenous

Mitochondria

Acute traumatic
coagulopathy

Immunology
Inflammation
Cellular responses
Molecular pathways

Fibrinolysis

Dilution

Consumption of
clot factors
Lymphocytes

Thrombocytes

Systemic
Pre-existing disease
Drugs and medications

Fig. 1

Trauma-induced
coagulopathy

Complex effects leading to trauma-induced coagulopathy

2011 British Journal of Surgery Society Ltd

Published by John Wiley & Sons Ltd

www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

896

K. Thorsen, K. G. Ringdal, K. Strand, E. Sreide, J. Hagemo and K. Sreide

Potential benets from hypothermia in patients with

major trauma have been claimed using arguments drawn
from elective surgery18 , cellular effects in experimental
studies19 , or extrapolation of the positive neurological
effects of clinically induced hypothermia used in cardiac
arrest19 23 . Recent ndings in traumatic brain injury
indicate that hypothermia may have protective effects in
some patients24 . In contrast to the effects and expanding
role seen in cardiac arrest survivors20,21,25 , the induction
of therapeutic hypothermia after major injury remains
experimental19,22 . The following sections will therefore
deal with spontaneous hypothermia.

Definition and classification

Post-traumatic hypothermia is generally considered to
be present in patients with a body core temperature
below 35 C26 28 . No uniform denition or classication
of hypothermia exists. Various cut-off values have
been proposed19,22,28 31 , although most studies refer to
hypothermia as less than 35 or 36 C26,32 . According
TM
to the ATLS
denition, hypothermia is dened as
a core body temperature below 35 C (95 F). In the
absence of concomitant traumatic injury (also called
accidental hypothermia), hypothermia is classied as
mild (3532 C or 95896 F), moderate (3230 C or
89686 F) or severe (below 30 C or 86 F). In injured
patients hypothermia should be considered to be any core
temperature below 36 C (968 F), and severe hypothermia
is any temperature below 32 C (896 F).
Hypothermia after injury is induced by either environmental exposure31 , the infusion of cold uids, or as a sideeffect of anaesthetic drugs affecting thermoregulation28,29 .
In civilian trauma, the effects of body/cavity exposure33 ,
development of hypovolaemia and the infusion of cold
uids are the most important factors contributing to temperature loss.

Incidence
Accurately estimating the true occurrence of hypothermia
in trauma patients is difcult because of inconsistent
documentation of core body temperature34 37 , variable
accuracy in measurements and inconsistent use of cut-off
levels for dening hypothermia.
Large retrospective studies indicate hypothermia on
admission in 16133 per cent of patients35,36,38 40 . A
large study from Pennsylvania identied 5 per cent of
38 520 trauma patients with hypothermia (dened as below
35 C)36 . A study of over 700 000 trauma patients in the
National Trauma Databank in the USA found hypothermia
2011 British Journal of Surgery Society Ltd
Published by John Wiley & Sons Ltd

of less than 35 C in 16 per cent and temperatures

below 32 C in only 802 patients (01 per cent)35 . Another
study from the same databank of 38 550 patients aged
1855 years found 85 per cent to have hypothermia on
admission39 . These data underscore that hypothermia is
not common in trauma patients overall.

Pathophysiological effects
Mild heat loss is usually well tolerated, with compensatory
pathophysiological changes to maintain temperature
homeostasis29 . Responses to mild hypothermia include
increased muscle tone and shivering, as well as metabolic
increases from the release of catecholamines and thyroxine.
Below 32 C, cardiac conduction disturbances become
apparent; atrial brillation is seen in about half of all
patients with a core temperature below 30 C. Serious
abnormal cardiac rhythms start to occur below about
28 C28,29 . At core temperatures lower than 28 C, the
respiratory rate dramatically decreases and myocardial
contractility is depressed. Slowing of the heart and
supraventricular arrhythmias may give way to ventricular
brillation and asystole18,30,41,42 . Hypothermia decreases
the enzymatic activity of clotting factors and impairs
platelet function. In addition, hypothermia inhibits
brinogen synthesis19,43 . Anaerobic metabolism results
in reduced adenosine 5
-triphosphate (ATP) synthesis,
leading to decreased hydrolysis of ATP to adenosine 5
diphosphate and decreased heat production19 .
Experimental studies have shown that thermoregulation
after injury is impaired as a result of a lowered hypothalamic
temperature threshold for the onset of shivering, which
results in no shivering, or only slight shivering, at about
31 C. Similarly, an impairment in the threshold for
vasoconstriction may also occur after trauma. In addition to
the effects of environmental exposure with increased heat
loss because of radiation, conduction and evaporation from
exposed body cavities, reduced muscle perfusion lowers
heat production28,44 . Some authors argue that, within the
most common temperature range of hypothermia seen in
trauma patients (3336 C), isolated hypothermia probably
has only a minimal clinical impact on haemostasis44 .

Effects on outcome
Several studies have shown an independent relationship
between death and hypothermia after trauma33,35,36,38,39,
45 47 . Non-survivors have a lower average body temperature, higher Injury Severity Score (ISS), and an increased
blood transfusion requirement35 . The core temperature
that has a clinical impact on trauma patients has not been
www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

Hypothermia, acidosis and coagulopathy in major injury

identied, but some retrospective studies have shown an

independent association with mortality in trauma patients
with an admission temperature below 35 C35,36,38 . However, these reports have not been consistent over time, as
others have not conrmed the association with death48,49 .
Despite the association between hypothermia, shock and
injury severity, some have argued that hypothermia itself is
only a weak independent predictor of mortality50 and that
hypothermia does not contribute to the incidence or degree
of post-traumatic coagulopathy51 . Others have argued that,
despite a lack of exact knowledge about the pathogenesis of
post-traumatic coagulopathy, signicant factors contributing to its development include tissue injury, hypoperfusion, clotting factor dilution, hypocalcaemia, hypothermia,
acidosis, inammation and brinolysis27,52 . Typical experimental effects of hypothermia alone, or in combination
with other factors of the lethal triad, on the ability to form
clots are shown in Fig. 2.
Acidosis

Control
Hypothermia
Acidosis
Hypothermia + acidosis

Poor

Ability to coagulate

Good

Metabolic acidosis in trauma is believed to be secondary

to tissue hypoxia in states of hypovolaemia and subsequent
inadequate tissue perfusion. In practice, the most obvious
indicator of metabolic acidosis in trauma is increased serum
concentration of lactate, which is produced in excessive
amounts as a result of increased anaerobic metabolism.
A number of problems may induce acidosis, notably
drug abuse (methanol, ethanol, cocaine), medications
(salicylates, penicillins), and medical conditions such
as hyperchloraemia, renal failure and ketoacidosis53 55 .
These factors need to be kept in mind in injured patients
with acidosis and no other obvious signs of a bleeding injury

Time to haemostasis

Modelling has demonstrated an additive negative effect of

factors contributing to coagulopathy

Fig. 2

2011 British Journal of Surgery Society Ltd

Published by John Wiley & Sons Ltd

897

or tissue hypoperfusion. The role of metabolic acidosis in

the lethal triad is complex. It is recognized as a marker
of inadequate resuscitation and impending organ failure,
but its direct relation to hypothermia and coagulopathy
is not entirely clear, except that all three are believed
mutually to perpetuate the state of shock preceding death
in exsanguinating trauma (Figs 1 and 2).

Definitions
Acidaemia is usually considered as an arterial pH below
736. Acidosis refers to the pathological condition that
results in acidaemia if there is no secondary compensatory
response to the primary disease process. The acidbase
balance in the blood is measured in an arterial blood sample,
usually taken shortly after admission in a trauma setting.
Hypoperfusion is the main contributor to acidosis with
increased lactate or a base decit (referred to as base excess
of less than 0). Although many factors may account for
increased values of both lactate and base excess, ongoing
bleeding should be suspected until proven otherwise in
patients presenting with deranged values after trauma (such
as a base decit of 5 or more).
The use of lactate and base decit as markers of
hypoperfusion has several limitations. Neither the cause
of the metabolic acidosis nor the type of disturbance
is uniquely identied. A more specic marker would be
better, but none is available. Tissue haemoglobin oxygen
saturation is currently being explored as a non-invasive
monitor of perfusion in the trauma setting and may provide
additional data on the cause of acidosis in trauma patients56 .
Bicarbonate and base decit levels also assume no
pre-existing disturbance in the non-bicarbonate buffers
(haemoglobin, magnesium). In a bleeding trauma patient,
these buffers are likely to be compromised, and up to
50 per cent of the acid load may be caused by acids other
than lactate57 .
Albumin can inuence the acidbase state, and a
decrease of 1 g/dl will raise the base decit by 37, which
might lead to an acidosis not recognized by standard measures. Consideration of weak acids such as phosphate and
albumin (including lactate) and arterial partial pressure
of carbon dioxide have led to the development of the
strong ion difference53 , originally proposed by Stewart.
This attempts to identify acidbase disorders not caused
by lactate. The Stewart calculation has not yet shown
any advantage over base decit, but it can be useful in
discriminating the cause of metabolic acidosis53 . Hyperchloraemic metabolic acidosis caused by saline infusion is
sometimes seen in trauma patients, and base decit does
not identify this as well as the Stewart (or modied Stewart)
www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

898

K. Thorsen, K. G. Ringdal, K. Strand, E. Sreide, J. Hagemo and K. Sreide

approach57 . Even though acidosis is known to induce coagulopathy (Fig. 2), an in vitro study on whole blood showed
that, without the presence of hypothermia, the effect of
acidosis was insignicant58 , although the blood samples
tested were from healthy volunteers.

Another demonstrated that the time needed to normalize

serum lactate levels was an important prognostic factor
for survival in severely injured patients. All patients whose
lactate levels normalized within 24 h survived, whereas
only three of 22 with persistently abnormal levels after
48 h survived74 .

Pathophysiological effects
Acidosis decreases cardiac contractility, attenuates adrenergic receptor responsiveness to inotropic agents, impairs
renal perfusion, and impairs coagulation as measured by the
time to clot and strength of the clot (Fig. 2)59 . The propagation phase of thrombin generation is inhibited, and
depletion of the platelet count occurs. These manifest as
prolonged clotting times and increased bleeding times43 .
The activity of the factor Xa/Va complex is reduced by
50 per cent at a pH of 72, 70 per cent at pH 70 and
90 per cent at pH 6860 . In addition, pH neutralization
does not completely correct coagulation, implying some
unknown effect of acidosis60 62 . These factors provide
strong evidence for acidosis as a major contributor to
coagulopathy.

Effects on outcome
Outcome assessments of acidosis per se are not easy. Few
studies have reported on this alone. Historical studies
have shown that the admission base decit in addition to
transfusion requirements during the rst 24 h correlate
signicantly with postinjury organ failure and death63 .
Severe initial lactic acidosis is associated with lower cardiac
performance and higher morbidity and mortality rates64 .
Base excess has been reported to be the best detector
of occult hypoperfusion (dened as hypoperfusion in the
presence of normal vital signs)65 . Abnormal base excess may
predict transfusion requirements, length of stay and need
for intensive care63 , but is hardly ever used in isolation for
decision-making or choice of therapy. Acidosis is usually
regarded as a poor prognostic sign66 , although severe
acidosis (pH < 66) has been reported with subsequent
survival after trauma67 .

Predictive models
Trauma score models have been developed to incorporate
base excess as a factor in the prediction of survival68 72 .
The predictive ability of one such model was not superior
to that of other existing models that did not include base
excess as a variable71 . One study recently reported on
the prehospital measurement of lactate for resuscitation
monitoring, without noting any difference in outcomes73 .
2011 British Journal of Surgery Society Ltd
Published by John Wiley & Sons Ltd

Coagulopathy

An understanding of coagulopathy in injured patients has

evolved with time75 , not least owing to lessons learned from
military experience ranging from the two World Wars to
recent conicts in Iraq and Afghanistan76 .
Coagulation of blood with the formation of a
haemostatic plug is traditionally described as a cascade of
events, where protein coagulation factors, initiated through
intrinsic or extrinsic pathways, interact in a sequential
manner to form a clot. This concept has been challenged,
and a cell-based model has been proposed whereby
haemostasis is thought to occur in three overlapping
phases, rather than in sequential steps, with an emphasis
on the crucial role of platelets. In the initiation phase,
exposure of tissue factor-bearing cells in the vessel wall or
in the circulation triggers activation of primary coagulation
factors (factors VII, X and V). The process undergoes
amplication as these factors adhere to and activate
the platelet membrane. During the propagation phase,
numerous factors are paired with their co-factors on
the platelet membrane, generating a burst of thrombin
production that nally converts brinogen to brin to
form an interlinked brin clot.

Definition
Haemostasis is dened as the control of bleeding without
pathological thrombotic events77 . Coagulopathy can then
be dened as any aw in the coagulation system,
leading to either increased bleeding time or increased
formation of clots. Many tests give information about
coagulation status, including platelet count, prothrombin
time, international normalized ratio, activated partial
thromboplastin time, d-dimer and brinogen levels. Most
were developed half a century ago to monitor haemophilia
and anticoagulation therapy, and have not been validated
for the prediction of haemorrhage in a clinical setting78 .
None is satisfactory in a trauma setting, as each takes
a considerable time to measure and represents a single
point in a potentially ongoing process of bleeding. By the
time the test results are available, the patient may already
have entered an irreversible state of hypothermia, acidosis
and coagulopathy. As a result, there is growing interest
www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

Hypothermia, acidosis and coagulopathy in major injury

899

in point-of-care testing, with capability for repeated

measurements and rapid results within minutes.

Pathophysiological effects
The simple synergy of hypothermia and acidosis in
a trauma setting leading to coagulopathy has been
challenged44,51,75,79 . Rather than a secondary effect of dilution and consumption as was believed in the past, traumainduced coagulopathy (TIC) is currently considered to
be a combination of primary (endogenous response) and
secondary (caused by dilution and consumption) events79
(Fig. 1). The early endogenous phase has been described as
acute traumatic coagulopathy (ATC), acute coagulopathy
of trauma shock and endogenous acute coagulopathy, all
of which describe the same entity44 . ATC is an impairment
of haemostasis that occurs early after injury and develops
endogenously in response to a combination of tissue damage and shock51,80 . It is associated with a fourfold higher
mortality rate, increased transfusion requirement and an
increased occurrence of organ failure81 83 .
The incidence of TIC depends on the methods
used to measure and dene the hypocoagulable or
hypercoagulable state. On admission to the hospital,
1034 per cent of trauma patients present with some
form of coagulopathy37,50,83,84 . TIC can lead to both

diffuse bleeding and the formation of clots, resulting in

microthrombosis. The condition resembles disseminated
intravascular coagulopathy (DIC), but with different
initiators and underlying mechanisms44 .

Mechanisms and pathways of trauma-induced

coagulopathy
Injuries induce perturbations in the coagulation system
in many ways85 . The protein C pathway seems to be an
important contributor to TIC when an injury is associated
with hypoperfusion80 , consistent with ndings in animal
models86 . Hypoperfusion induces expression of thrombomodulin on the endothelial cell wall. Following the
thrombin burst, thrombin combines with thrombomodulin
and the endothelial protein C receptor. This complex
activates protein C, which probably plays an essential role
by inhibiting factors V, VIII and plasminogen activator
inhibitor 1, causing a hypocoagulable and hyperbrinolytic
state (Fig. 3). It is possible to inhibit this pathway, in the
hope of reversing the state of ATC. The problem, however,
is that protein C also seems to have a cytoprotective
role strongly correlated with survival86 . There may
be an increased risk of developing ventilator-associated
pneumonia with low levels of protein C87 . Therapeutic
inhibition of this pathway is not yet possible without loss of

Fibrinogen

Fibrin

Activation of platelets

Clot formation

Factor Va

Injury +
hypoperfusion

Activation of
Factor VIIIa

Factor Va

Thrombin

aPC

PC

Factor PAI-1

Thrombomodulin

Coagulopathy

Factor VIIIa

Hyperfibrinolysis

EPCR

Endothelial cells

Simple overview of the thrombinthrombomodulin complex and protein C (PC) in inducing coagulopathy after trauma. Injury
and hypoperfusion induce excess expression of thrombomodulin on the endothelial cell wall. Following a thrombin burst, thrombin
combines with thrombomodulin and the endothelial protein C receptor (EPCR); this complex activates protein C. Activated protein C
(aPC) probably plays an essential role by inhibiting factors V, VIII and plasminogen activator inhibitor (PAI) 1, causing a
hypocoagulable and hyperbrinolytic state

Fig. 3

2011 British Journal of Surgery Society Ltd

Published by John Wiley & Sons Ltd

www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

900

K. Thorsen, K. G. Ringdal, K. Strand, E. Sreide, J. Hagemo and K. Sreide

the cytoprotective mechanisms, nor is selective inhibition

of the anticoagulant part of protein C.
Opponents of the concept of the protein C pathway
argue that coagulopathy in trauma is simply a manifestation
of DIC, with a brinolytic phenotype combined with
coagulation factor depletion88 . Further, they point out
that any state of serious systemic hypoperfusion induces
excessive brinolysis but, in the presence of haemorrhage,
factor depletion plays a more prominent role.
The role of platelets in trauma is also not yet resolved. A
major bleeding episode can easily result in insufcient
platelet levels. Thrombocytopenia at admission after
trauma has been linked to increased mortality, and the
highest survival rates are seen in patients receiving the
highest platelet to erythrocyte ratio of transfusion89 .
Although platelet counts and outcome do correlate, little
is known about the potential mechanisms behind this
association. Function is probably more important than the
absolute platelet count. Platelet function is to some extent
reected by viscoelastic haemostatic assays (VHAs) such as
thromboelastography (TEG ; Haemoscope Corporation,
Niles, Illinois, USA) and rotational thromboelastometry
(ROTEM ; Pentapharm, Munich, Germany)78 . Tests of
platelet aggregation (Multiplate , Verum Diagnostica,
Munich, Germany; PFA-100 , Dade Behring, Marburg,
Germany) may give additional information, especially
when platelet inhibitors are present, although this has
not been investigated thoroughly in the trauma setting90 .
The cell-based model of coagulation emphasizes the
role of platelets in brin formation through the cascade
of events taking place on the thrombocyte membrane.
Platelets are probably the most important factors involved
in coagulation. Despite this, the role of platelets in
TIC is poorly investigated and management guidelines
are ambiguous81,91 . Yet, the trend in massive transfusion
protocols worldwide has been towards the early addition
of platelets in a ratio approaching 1 : 1 : 1 for packed red
blood cells to fresh frozen plasma to thrombocytes92 94 .
Fibrinogen levels, the formation of brin and traumainduced brinolysis have been central in the investigation
of traumatic coagulopathy43,61,95 . Primary brinolysis
appears to be fundamental in TIC and occurs early
(less than 1 h) after trauma. Fibrinolysis is associated
with massive transfusion requirements, coagulopathy and
haemorrhage-related death96 . Trauma alters brinogen
metabolism in a variety of ways43 . Ongoing haemorrhage
may cause accelerated brinogen breakdown. Loss of blood
and decreases in core body temperature inhibit brinogen
synthesis, and acidosis causes accelerated brinogen
breakdown. Haemorrhage, hypothermia and acidosis all
result in reduced availability of brinogen, supporting the

notion of brinogen supplementation in trauma patients

with coagulation defects43,62 . In this regard, point-ofcare testing with thromboelastography seems crucial in
identifying coagulation abnormalities at an early stage.
When evaluating whole blood in the uid phase after
a traumatic insult, there is research that suggests an
association between coagulopathy and ISS. A near linear
relationship has been shown to exist between the degree
of coagulopathy and increasing ISS83 . This association
is even stronger when adding hypothermia, acidosis and
hypotension to severity of injury97 .

2011 British Journal of Surgery Society Ltd

Published by John Wiley & Sons Ltd

www.bjs.co.uk

Early diagnosis and point-of-care testing

TEG , ROTEM and the Sonoclot Coagulation &
Platelet Function Analyzer (Sienco, Arvada, Colorado,
USA) are all VHAs that may function as bedside diagnostic tools52,78,90 . Rapid thromboelastography (thromboelastography with added tissue factor) is an alternative,
together with several other modications for this technology. The most widely explored and used technologies are
TEG and ROTEM78 . These instruments measure and
reproduce the phenomenon of clotting in graphical and/or
numerical format (Figs 4 and 5).
The advantages of VHAs are many, and include
evaluation of the coagulation system in whole blood. The
endpoint is clinically relevant, that is clotting in whole
blood (brin formation, clot retraction and brinolysis).
The results are available quickly (in about 20 min for rapid

Coagulation
Time

Kinetics

Fibrinolysis
Strength

Lysis

K
TEG

R
CT

MA
MCF

Ly
CL

ROTEM
CFT

Clotting evaluation by thromboelastography (TEG ).

Schematic trace indicating the commonly reported variables
reaction time (R)/clotting time (CT), clot formation time (K,
CFT), angle , maximum amplitude (MA)/maximum clot
rmness (MCF) and lysis (Ly)/clot lysis (CL). Examples for
reading include TEG (upper part) and rotational
thromboelastometry (ROTEM ) (lower part). With slight
modications and reproduced with permission from Johansson
et al.78

Fig. 4

British Journal of Surgery 2011; 98: 894907

Hypothermia, acidosis and coagulopathy in major injury

901

10 mm

R
min
62
28

K
min
19
13

Angle
degrees
627
55 78

MA
mm
611
51 69

PMA
00

G
d/sc
79K
46K 109K

EPL
%
07
0 15

A
mm
555

CI
03
3 3

LY30
%
07
08

Normal
10 mm

R
min
64
28

K
min
17
13

Angle
degrees
656
55 78

MA
mm
256
51 69

PMA
00

G
d/sc
17K
46K 109K

EPL
%
974
0 15

A
mm
07

CI
45
3 3

LY30
%
923
08

Hyperfibrinolysis
10 mm

R
min
201
28

K
min
106
13

Angle
degrees
200
55 78

MA
mm
451
51 69

PMA
10

G
d/sc
41K
46K 109K

EPL
%
35
0 15

A
mm
435

CI
178
3 3

LY30
%
07
08

Hypocoagulable

Examples of thromboelastography readings: a normal clotting status, b hyperbrinolysis and c hypocoagulable state. R, reaction
time (period of latency between placing blood sample in analyser and initial brin formation); K, clot kinetics (clot formation time, or a
measure of the time to reach a specic level of clot strength); MA, maximum amplitude; G, measure of clot strength (a direct function
of the maximum dynamic properties of brin and platelet bonding via GPIIb/IIIa representing the ultimate strength of the brin clot);
CI, coagulation index (a linear combination of clot time, clot kinetics and clot strength); LY30, brinolytic prole (measures the rate of
amplitude reduction 30 min after MA)
Fig. 5

2011 British Journal of Surgery Society Ltd

Published by John Wiley & Sons Ltd

www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

902

K. Thorsen, K. G. Ringdal, K. Strand, E. Sreide, J. Hagemo and K. Sreide

thromboelastography)98 , making them potentially relevant

for clinical decision-making in the trauma setting.
The use of VHAs is not new in surgery, and extensive
experience has been obtained in elective cardiac and
liver surgery78 . In terms of its use as a guide for
massive transfusion protocols in severely injured patients,
however, the evidence is just emerging52,78,98,99 . VHAs
cannot detect the effects on platelet function related to
commonly used drugs such as clopidogrel, non-steroidal
anti-inammatory drugs and aspirin. As the assay is usually
performed at a constant temperature of 37 C (although it
may be calibrated to the patients actual temperature),
the effect of hypothermia is not recognized in this
system.

Implications for fluid therapy

Blood component therapy, or haemostatic damage
control resuscitation13,100 103 , has received renewed
interest after favourable reports in military situations.
Outcomes in civilian trauma have been conicting so
far104 106 . Although a ratio of 1 : 1 for packed red
cells to plasma (and platelets) seems to be widely
supported93,107 , there is no rm evidence for this in civilian
trauma92,104,108 111 . On the contrary, this protocol has
been shown to be harmful when administered to the wrong
patients112 , with an increase in complications and organ
dysfunction.
Recent trials have investigated the effects of other
additions during resuscitation. A randomized study
of over 20 000 patients compared tranexamic acid
(an antibrinolytic agent) with placebo for correction
of brinolysis. There was a reduction in both allcause mortality and bleeding-related mortality compared
with controls, with no increase in fatal thrombotic
events113 . In the CONTROL trial114 , activated factor
VIIa (NovoSeven ; Novo Nordisk, Bagsvrd, Denmark)
reduced the amount of blood product used compared with
placebo, but did not affect mortality. The generalizability
of these studies is hampered by their design (selection
of study population, study centres, accrual of patients,
level and expertise of provider care, lack of standardized
measurements, criteria for presence or severity of
coagulopathy). A recent multicentre study found activated
factor VII to be of little or no use in patients
with sustained shock, acidosis and a low platelet
count115 .
Goal-directed therapy to correct coagulopathy after
trauma seems warranted in selected patients, but the best
choice of agent is still not known.
2011 British Journal of Surgery Society Ltd
Published by John Wiley & Sons Ltd

Discussion

The human response to trauma, involving a complex

of physiological, biochemical, immunological and cellular mechanisms, may be unpredictable116 . Protracted
reduction in tissue perfusion after major trauma produces
profound effects on tissue metabolism, structure and function that become apparent at cellular, organ and systemic
levels85,117 .
The treatment of hypothermic, hypotensive and
acidotic trauma patients in a coagulopathic state is
particularly challenging. Understanding the lethal triad
is paramount in order to provide timely and optimal
care for injured patients. Implementation of standard
measurements of hypothermia, acidosis and coagulopathy
(or their appropriate surrogate markers) that are easy to
use and interpret in prognostication and decision-making
can then follow. In turn, this leads to more logical timing
and composition of uids and blood products used in
resuscitation for these patients.
Pathophysiological derangements after trauma occur at
an earlier stage than previously thought. Coagulopathy is
present in the emergency room even in less severely injured
patients before the administration of large amounts of
uid83 . A recent systematic evaluation of the experimental
coagulopathy studies has, however, led to a consensus
suggestion of a list of crucial factors to consider in
promoting the appropriate use of translational models of
haemorrhage and shock118 .
The inclusion of hypothermia, acidosis and coagulopathy in formal scores for outcome prediction has not been
widely entertained, but could be useful if available through
bedside measurements. Some recently developed scoring
tools have included surrogate measures for such factors (for
example base excess) in prediction models68 70,119 , such as
the Sequential Trauma Score, Emergency Trauma Score,
Revised Injury Severity Classication Score119 , Trauma
Associated Severe Haemorrhage score120 and Base Excess
Injury Severity Scale. Validation of such scores is needed to
assess their usefulness in the general trauma population121 .
The treatment of cold, hypotensive trauma patients,
admitted in shock with coagulopathy, is complex, difcult to handle and associated with increased mortality82 .
A number of institutional, societal and regional
guidelines27,94,101,107,122 129 have been established and
revised to provide guidance in decision-making, although
little is known about their implementation and use in real
life. Work still needs to be done to nd reliable tests that
quickly identify these patients. They often make heavy
demands on transfusion services in terms of requirements
for blood and its components that cannot always be met.
www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

Hypothermia, acidosis and coagulopathy in major injury

It follows that there is an equally important need to devise

therapies that unequivocally lead to better survival.
Goal-directed therapy to correct coagulopathy in trauma
seems warranted, but patient selection, timing, ratio of
blood products and choice of adjunct agent is not resolved
from current trials130 . Cellular preservation techniques by
way of therapeutic cooling or molecular inhibition may add
further to benets derived from blood component therapy
for severely injured patients when appropriate diagnostic
tools are available in the future.

Acknowledgements

The authors declare no conict of interest.

References
1 Sreide K. Epidemiology of major trauma. Br J Surg 2009;
96: 697698.
2 Bansal V, Fortlage D, Lee JG, Costantini T, Potenza B,
Coimbra R. Hemorrhage is more prevalent than brain
injury in early trauma deaths: the golden six hours. Eur J
Trauma Emerg Surg 2009; 1: 2630.
3 de Knegt C, Meylaerts SA, Leenen LP. Applicability of the
trimodal distribution of trauma deaths in a Level I trauma
centre in the Netherlands with a population of mainly blunt
trauma. Injury 2008; 39: 9931000.
4 Pang JM, Civil I, Ng A, Adams D, Koelmeyer T. Is the
trimodal pattern of death after trauma a dated concept in
the 21st century? Trauma deaths in Auckland 2004. Injury
2008; 39: 102106.
5 Pfeifer R, Tarkin IS, Rocos B, Pape HC. Patterns of
mortality and causes of death in polytrauma patients has
anything changed? Injury 2009; 40: 907911.

6 Sreide K, Kruger
AJ, Vardal AL, Ellingsen CL, Sreide E,
Lossius HM. Epidemiology and contemporary patterns of
trauma deaths: changing place, similar pace, older face.
World J Surg 2007; 31: 20922103.
7 Eastridge BJ, Salinas J, McManus JG, Blackburn L,
Bugler EM, Cooke WH et al. Hypotension begins at
110 mm Hg: redening hypotension with data. J Trauma
2007; 63: 291297.
8 Sreide K. Three decades (19782008) of Advanced
Trauma Life Support (ATLS) practice revised and evidence
revisited. Scand J Trauma Resusc Emerg Med 2008; 16: 19.
9 Lechleuthner A, Lefering R, Bouillon B, Lentke E,
Vorweg M, Tiling T. Prehospital detection of uncontrolled
haemorrhage in blunt trauma. Eur J Emerg Med 1994; 1:
1318.
10 Guly HR, Bouamra O, Little R, Dark P, Coats T,
Driscoll P et al. Testing the validity of the ATLS
classication of hypovolaemic shock. Resuscitation 2010; 81:
11421147.

2011 British Journal of Surgery Society Ltd

Published by John Wiley & Sons Ltd

903

11 Davis JW, Davis IC, Bennink LD, Bilello JF, Kaups KL,
Parks SN. Are automated blood pressure measurements
accurate in trauma patients? J Trauma 2003; 55: 860863.
12 Seamon MJ, Feather C, Smith BP, Kulp H, Gaughan JP,
Goldberg AJ. Just one drop: the signicance of a single
hypotensive blood pressure reading during trauma
resuscitations. J Trauma 2010; 68: 12891294.
13 Duchesne JC, McSwain NE Jr, Cotton BA, Hunt JP,
Dellavolpe J, Lafaro K et al. Damage control resuscitation:
the new face of damage control. J Trauma 2010; 69:
976990.
14 Rotondo MF, Zonies DH. The damage control sequence
and underlying logic. Surg Clin North Am 1997; 77:
761777.
15 Rosenfeld JV. Damage control neurosurgery. Injury 2004;
35: 655660.
16 Giannoudis PV, Giannoudi M, Stavlas P. Damage control
orthopaedics: lessons learned. Injury 2009; 40(Suppl 4):
S47S52.
17 den Hartog AW, de Pont AC, Robillard LB, Binnekade JM,
Schultz MJ, Horn J. Spontaneous hypothermia on intensive
care unit admission is a predictor of unfavorable
neurological outcome in patients after resuscitation: an
observational cohort study. Crit Care 2010; 14: R121.
18 Hildebrand F, Giannoudis PV, van Griensven M,
Chawda M, Pape HC. Pathophysiologic changes and effects
of hypothermia on outcome in elective surgery and trauma
patients. Am J Surg 2004; 187: 363371.
19 Kheirbek T, Kochanek AR, Alam HB. Hypothermia in
bleeding trauma: a friend or a foe? Scand J Trauma Resusc
Emerg Med 2009; 17: 65.
20 Behringer W, Arrich J, Holzer M, Sterz F. Out-of-hospital
therapeutic hypothermia in cardiac arrest victims. Scand J
Trauma Resusc Emerg Med 2009; 17: 52.
21 Kamarainen A, Hoppu S, Silfvast T, Virkkunen I.
Prehospital therapeutic hypothermia after cardiac
arrest from current concepts to a future standard. Scand J
Trauma Resusc Emerg Med 2009; 17: 53.
22 Fukudome EY, Alam HB. Hypothermia in multisystem
trauma. Crit Care Med 2009; 37(Suppl): S265S272.
23 Janata A, Holzer M. Hypothermia after cardiac arrest. Prog
Cardiovasc Dis 2009; 52: 168179.
24 Nichol AD, Cooper DJ. Can we improve neurological
outcomes in severe traumatic brain injury? Something old
(early prophylactic hypothermia) and something new
(erythropoietin). Injury 2009; 40: 471478.
25 Busch M, Soreide E, Lossius HM, Lexow K, Dickstein K.
Rapid implementation of therapeutic hypothermia in
comatose out-of-hospital cardiac arrest survivors. Acta
Anaesthesiol Scand 2006; 50: 12771283.
26 American College of Surgeons Committee on Trauma.
Advanced Trauma Life Support for Doctors. Students Course
Manual (7th edn). American College of Surgeons
Committee on Trauma: Chicago, 2004.
27 Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J,
Fernandez-Mondejar E et al. Management of bleeding

www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

904

28

29
30
31
32

33

34

35

36

37

38

39

40

41

42
43

K. Thorsen, K. G. Ringdal, K. Strand, E. Sreide, J. Hagemo and K. Sreide

following major trauma: an updated European guideline.

Crit Care 2010; 14: R52.
Sreide E, Smith CE. Hypothermia in trauma. In Trauma
Anesthesia, Smith CE (ed). Cambridge University Press:
Cambridge, 2008; 445464.
Tsuei BJ, Kearney PA. Hypothermia in the trauma patient.
Injury 2004; 35: 715.
Danzl DF, Pozos RS. Accidental hypothermia. N Engl J
Med 1994; 331: 17561760.
Jurkovich GJ. Environmental cold-induced injury. Surg Clin
North Am 2007; 87: 247267, viii.
Nolan JP, Soar J, Zideman DA, Biarent D, Bossaert LL,
Deakin C et al. European Resuscitation Council Guidelines
for Resuscitation 2010 Section 1. Executive summary.
Resuscitation 2010; 81: 12191276.
Inaba K, Teixeira PG, Rhee P, Brown C, Salim A, DuBose J
et al. Mortality impact of hypothermia after cavitary
explorations in trauma. World J Surg 2009; 33: 864869.
Lossius HM, Langhelle A, Sreide E, Pillgram-Larsen J,
Lossius TA, Laake P et al. Reporting data following major
trauma and analysing factors associated with outcome using
the new Utstein style recommendations. Resuscitation 2001;
50: 263272.
Martin RS, Kilgo PD, Miller PR, Hoth JJ, Meredith JW,
Chang MC. Injury-associated hypothermia: an analysis of
the 2004 National Trauma Data Bank. Shock 2005; 24:
114118.
Wang HE, Callaway CW, Peitzman AB, Tisherman SA.
Admission hypothermia and outcome after major trauma.
Crit Care Med 2005; 33: 12961301.
Maegele M, Lefering R, Yucel N, Tjardes T, Rixen D,
Paffrath T et al.; AG Polytrauma of the German Trauma
Society (DGU). Early coagulopathy in multiple injury: an
analysis from the German Trauma Registry on 8724
patients. Injury 2007; 38: 298304.
Aitken LM, Hendrikz JK, Dulhunty JM, Rudd MJ.
Hypothermia and associated outcomes in seriously injured
trauma patients in a predominantly sub-tropical climate.
Resuscitation 2009; 80: 217223.
Sha S, Elliott AC, Gentilello L. Is hypothermia simply a
marker of shock and injury severity or an independent risk
factor for mortality in trauma patients? Analysis of a large
national trauma registry. J Trauma 2005; 59: 10811085.
Ireland S, Endacott R, Cameron P, Fitzgerald M, Paul E.
The incidence and signicance of accidental hypothermia in
major trauma a prospective observational study.
Resuscitation 2011; 82: 300306.
Biem J, Koehncke N, Classen D, Dosman J. Out of the
cold: management of hypothermia and frostbite. CMAJ
2003; 168: 305311.
Mallet ML. Pathophysiology of accidental hypothermia.
QJM 2002; 95: 775785.
Martini WZ. Fibrinogen metabolic responses to trauma.
Scand J Trauma Resusc Emerg Med 2009; 17: 2.

2011 British Journal of Surgery Society Ltd

Published by John Wiley & Sons Ltd

44 Hess JR, Brohi K, Dutton RP, Hauser CJ, Holcomb JB,

Kluger Y et al. The coagulopathy of trauma: a review of
mechanisms. J Trauma 2008; 65: 748754.
45 Bernabei AF, Levison MA, Bender JS. The effects of
hypothermia and injury severity on blood loss during
trauma laparotomy. J Trauma 1992; 33: 835839.
46 Jurkovich GJ, Greiser WB, Luterman A, Curreri PW.
Hypothermia in trauma victims: an ominous predictor of
survival. J Trauma 1987; 27: 10191024.
47 Gentilello LM, Jurkovich GJ, Stark MS, Hassantash SA,
OKeefe GE. Is hypothermia in the victim of major trauma
protective or harmful? A randomized, prospective study.
Ann Surg 1997; 226: 439447.
48 Steinemann S, Shackford SR, Davis JW. Implications of
admission hypothermia in trauma patients. J Trauma 1990;
30: 200202.
49 Beilman GJ, Blondet JJ, Nelson TR, Nathens AB,
Moore FA, Rhee P et al. Early hypothermia in severely
injured trauma patients is a signicant risk factor for
multiple organ dysfunction syndrome but not mortality.
Ann Surg 2009; 249: 845850.
50 Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of
trauma: mechanism, identication and effect. Curr Opin Crit
Care 2007; 13: 680685.
51 Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M,
Mackersie RC et al. Acute coagulopathy of trauma:
hypoperfusion induces systemic anticoagulation and
hyperbrinolysis. J Trauma 2008; 64: 12111217.
52 Kashuk JL, Moore EE, Sawyer M, Le T, Johnson J,
Bif WL et al. Postinjury coagulopathy management: goal
directed resuscitation via POC thrombelastography. Ann
Surg 2010; 251: 604614.
53 Zehtabchi S, Soghoian S, Sinert R. Utility of Stewarts
strong ion difference as a predictor of major injury after
trauma in the ED. Am J Emerg Med 2007; 25: 938941.
54 Jones RC, Yost MJ, Fann SA. Cocaine induced acidosis in
the trauma patient: a potential confounding factor. Am Surg
2008; 74: 11251127.
55 Funk GC, Doberer D, Kneidinger N, Lindner G,
Holzinger U, Schneeweiss B. Acidbase disturbances in
critically ill patients with cirrhosis. Liver Int 2007; 27:
901909.
56 Santora RJ, Moore FA. Monitoring trauma and intensive
care unit resuscitation with tissue hemoglobin oxygen
saturation. Crit Care 2009; 13(Suppl 5): S10.
57 Kaplan LJ, Cheung NH, Maerz L, Lui F, Schuster K,
Luckianow G et al. A physicochemical approach to
acidbase balance in critically ill trauma patients minimizes
errors and reduces inappropriate plasma volume expansion.
J Trauma 2009; 66: 10451051.

58 Dirkmann D, Hanke AA, Gorlinger

K, Peters J.
Hypothermia and acidosis synergistically impair coagulation
in human whole blood. Anesth Analg 2008; 106: 16271632.
59 Engstrom M, Schott U, Romner B, Reinstrup P. Acidosis
impairs the coagulation: a thromboelastographic study. J
Trauma 2006; 61: 624628.

www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

Hypothermia, acidosis and coagulopathy in major injury

60 Hess JR, Holcomb JB, Hoyt DB. Damage control

resuscitation: the need for specic blood products to treat
the coagulopathy of trauma. Transfusion 2006; 46: 685686.
61 Martini WZ, Holcomb JB. Acidosis and coagulopathy: the
differential effects on brinogen synthesis and breakdown in
pigs. Ann Surg 2007; 246: 831835.
62 Martini WZ. Coagulopathy by hypothermia and acidosis:
mechanisms of thrombin generation and brinogen
availability. J Trauma 2009; 67: 202208.
63 Davis JW, Parks SN, Kaups KL, Gladen HE,
ODonnell-Nicol S. Admission base decit predicts
transfusion requirements and risk of complications. J
Trauma 1996; 41: 769774.
64 Blow O, Magliore L, Claridge JA, Butler K, Young JS. The
golden hour and the silver day: detection and correction of
occult hypoperfusion within 24 hours improves outcome
from major trauma. J Trauma 1999; 47: 964969.
65 Thom O, Taylor DM, Wolfe RE, Myles P, Krum H,
Wolfe R. Pilot study of the prevalence, outcomes and
detection of occult hypoperfusion in trauma patients. Emerg
Med J 2010; 27: 470472.
66 Kaplan LJ, Kellum JA. Initial pH, base decit, lactate, anion
gap, strong ion difference, and strong ion gap predict
outcome from major vascular injury. Crit Care Med 2004;
32: 11201124.
67 Willcox N, Oakley P. Survival with an arterial pH of 657
following major trauma with exsanguinating haemorrhage
associated with traumatic amputation. Resuscitation 2002; 53:
217221.
68 Huber-Wagner S, Stegmaier J, Mathonia P, Paffrath T,
Euler E, Mutschler M et al. The sequential trauma score a
new instrument for the sequential mortality prediction in
major trauma. Eur J Med Res 2010; 15: 185195.
69 Raum MR, Nijsten MW, Vogelzang M, Schuring F,
Lefering R, Bouillon B et al.; Polytrauma Study Group of
the German Trauma Society. Emergency trauma score: an
instrument for early estimation of trauma severity. Crit Care
Med 2009; 37: 19721977.
70 Kroezen F, Bijlsma TS, Liem MS, Meeuwis JD,
Leenen LP. Base decit-based predictive modeling of
outcome in trauma patients admitted to intensive care units
in Dutch trauma centers. J Trauma 2007; 63: 908913.
71 Guzzo JL, Bochicchio GV, Napolitano LM, Malone DL,
Meyer W, Scalea TM. Prediction of outcomes in trauma:
anatomic or physiologic parameters? J Am Coll Surg 2005;
201: 891897.
72 Rutherford EJ, Morris JA Jr, Reed GW, Hall KS. Base
decit straties mortality and determines therapy. J Trauma
1992; 33: 417423.
73 Jousi M, Reitala J, Lund V, Katila A, Leppaniemi A. The
role of pre-hospital blood gas analysis in trauma
resuscitation. World J Emerg Surg 2010; 5: 10.
74 Abramson D, Scalea TM, Hitchcock R, Trooskin SZ,
Henry SM, Greenspan J. Lactate clearance and survival
following injury. J Trauma 1993; 35: 584588.

2011 British Journal of Surgery Society Ltd

Published by John Wiley & Sons Ltd

905

75 Tieu BH, Holcomb JB, Schreiber MA. Coagulopathy: its

pathophysiology and treatment in the injured patient. World
J Surg 2007; 31: 10551064.
76 Hoyt DB. Blood and war lest we forget. J Am Coll Surg
2009; 209: 681686.
77 Levy JH, Dutton RP, Hemphill JC III, Shander A,
Cooper D, Paidas MJ et al.; Hemostasis Summit
Participants. Multidisciplinary approach to the challenge of
hemostasis. Anesth Analg 110: 354364.
78 Johansson PI, Stissing T, Bochsen L, Ostrowski SR.
Thrombelastography and thromboelastometry in assessing
coagulopathy in trauma. Scand J Trauma Resusc Emerg Med
2009; 17: 45.
79 MacLeod JB. Trauma and coagulopathy: a new paradigm to
consider. Arch Surg 2008; 143: 797801.
80 Brohi K, Cohen MJ, Ganter MT, Matthay MA,
Mackersie RC, Pittet JF. Acute traumatic coagulopathy:
initiated by hypoperfusion: modulated through the protein
C pathway? Ann Surg 2007; 245: 812818.
81 Davenport RA, Brohi K. Coagulopathy in trauma patients:
importance of thrombocyte function? Curr Opin Anaesthesiol
2009; 22: 261266.
82 MacLeod JB, Lynn M, McKenney MG, Cohn SM,
Murtha M. Early coagulopathy predicts mortality in
trauma. J Trauma 2003; 55: 3944.
83 Brohi K, Singh J, Heron M, Coats T. Acute traumatic
coagulopathy. J Trauma 2003; 54: 11271130.
84 Brohi K. Diagnosis and management of coagulopathy after
major trauma. Br J Surg 2009; 96: 963964.
85 Chaudry IH, Bland KI. Cellular mechanisms of injury after
major trauma. Br J Surg 2009; 96: 10971098.
86 Chesebro BB, Rahn P, Carles M, Esmon CT, Xu J, Brohi K
et al. Increase in activated protein C mediates acute
traumatic coagulopathy in mice. Shock 2009; 32: 659665.
87 Cohen MJ, Bir N, Rahn P, Dotson R, Brohi K,
Chesebro BB et al. Protein C depletion early after trauma
increases the risk of ventilator-associated pneumonia. J
Trauma 2009; 67: 11761181.
88 Gando S. Acute coagulopathy of trauma shock and
coagulopathy of trauma: a rebuttal. You are now going
down the wrong path. J Trauma 2009; 67: 381383.
89 Johansson PI, Ostrowski SR, Secher NH. Management of
major blood loss: an update. Acta Anaesthesiol Scand 2010;
54: 10391049.
90 Ganter MT, Hofer CK. Coagulation monitoring: current
techniques and clinical use of viscoelastic point-of-care
coagulation devices. Anesth Analg 2008; 106: 13661375.
91 Jacoby RC, Owings JT, Holmes J, Battistella FD,
Gosselin RC, Paglieroni TG. Platelet activation and
function after trauma. J Trauma 2001; 51: 639647.
92 Phan HH, Wisner DH. Should we increase the ratio of
plasma/platelets to red blood cells in massive transfusion:
what is the evidence? Vox Sang 2010; 98: 395402.
93 Mitra B, Mori A, Cameron PA, Fitzgerald M, Paul E,
Street A. Fresh frozen plasma (FFP) use during massive

www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

906

94

95

96

97

98

99

100

101
102

103

104

105

106

107

K. Thorsen, K. G. Ringdal, K. Strand, E. Sreide, J. Hagemo and K. Sreide

blood transfusion in trauma resuscitation. Injury 2010; 41:

3539.
Greer SE, Rhynhart KK, Gupta R, Corwin HL. New
developments in massive transfusion in trauma. Curr Opin
Anaesthesiol 2010; 23: 246250.

Schochl
H, Frietsch T, Pavelka M, Jambor C.
Hyperbrinolysis after major trauma: differential diagnosis
of lysis patterns and prognostic value of thrombelastometry.
J Trauma 2009; 67: 125131.
Kashuk JL, Moore EE, Sawyer M, Wohlauer M, Pezold M,
Barnett C et al. Primary brinolysis is integral in the
pathogenesis of the acute coagulopathy of trauma. Ann Surg
2010; 252: 434444.
Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M,
Burch JM, Galloway B. Predicting life-threatening
coagulopathy in the massively transfused trauma patient:
hypothermia and acidoses revisited. J Trauma 1997; 42:
857861.
Jeger V, Zimmermann H, Exadaktylos AK. Can RapidTEG
accelerate the search for coagulopathies in the patient with
multiple injuries? J Trauma 2009; 66: 12531257.
Schoechl H, Nienaber U, Hofer G, Voelckel W, Jambor C,
Scharbert G et al. Goal-directed coagulation management
of major trauma patients using rotation thromboelastometry
(ROTEM)-guided administration of brinogen and
prothrombin complex concentrate. Crit Care 2010; 14: R55.
Johansson PI, Stensballe J. Hemostatic resuscitation for
massive bleeding: the paradigm of plasma and platelets a
review of the current literature. Transfusion 2010; 50:
701710.
Sihler KC, Napolitano LM. Massive transfusion: new
insights. Chest 2009; 136: 16541667.
Holcomb JB, Jenkins D, Rhee P, Johannigman J,
Mahoney P, Mehta S et al. Damage control resuscitation:
directly addressing the early coagulopathy of trauma.
J Trauma 2007; 62: 307310.
Dries DJ. The contemporary role of blood products and
components used in trauma resuscitation. Scand J Trauma
Resusc Emerg Med 2010; 18: 63.
Dirks J, Jorgensen H, Jensen CH, Ostrowski SR,
Johansson PI. Blood product ratio in acute traumatic
coagulopathy effect on mortality in a Scandinavian level 1
trauma centre. Scand J Trauma Resusc Emerg Med 2010; 18:
65.
Scalea TM, Bochicchio KM, Lumpkins K, Hess JR,
Dutton R, Pyle A et al. Early aggressive use of fresh frozen
plasma does not improve outcome in critically injured
trauma patients. Ann Surg 2008; 248: 578584.
Holcomb JB, Wade CE, Michalek JE, Chisholm GB,
Zarzabal LA, Schreiber MA et al. Increased plasma and
platelet to red blood cell ratios improves outcome in 466
massively transfused civilian trauma patients. Ann Surg
2008; 248: 447458.
Munro AR, Ferguson C. Towards evidence based
emergency medicine: best BETs from the Manchester
Royal Inrmary. BET 1: blood component therapy in

2011 British Journal of Surgery Society Ltd

Published by John Wiley & Sons Ltd

108

109

110

111

112

113

114

115

116

117

118

119

120

trauma patients requiring massive transfusion. Emerg Med J

2010; 27: 5355.
Schuster KM, Davis KA, Lui FY, Maerz LL, Kaplan LJ.
The status of massive transfusion protocols in United States
trauma centers: massive transfusion or massive confusion?
Transfusion 2010; 50: 15451551.
Davenport R, Curry N, Manson J, DeAth H, Coates A,
Rourke C et al. Hemostatic effects of fresh frozen plasma
may be maximal at red cell ratios of 1 : 2. J Trauma 2011;
70: 9095.
Stanworth SJ, Morris TP, Gaarder C, Goslings JC,
Maegele M, Cohen MJ et al. Reappraising the concept of
massive transfusion in trauma. Crit Care 2010; 14: R239.
Allen SR, Kashuk JL. Unanswered questions in the use of
blood component therapy in trauma. Scand J Trauma Resusc
Emerg Med 2011; 19: 5.
Inaba K, Branco BC, Rhee P, Blackbourne LH,
Holcomb JB, Teixeira PG et al. Impact of plasma
transfusion in trauma patients who do not require massive
transfusion. J Am Coll Surg 2010; 210: 957965.
Shakur H, Roberts I, Bautista R, Caballero J, Coats T,
Dewan Y et al. Effects of tranexamic acid on death, vascular
occlusive events, and blood transfusion in trauma patients
with signicant haemorrhage (CRASH-2): a randomised,
placebo-controlled trial. Lancet 2010; 376: 2332.
Hauser CJ, Boffard K, Dutton R, Bernard GR, Croce MA,
Holcomb JB et al.; CONTROL Study Group. Results of
the CONTROL trial: efcacy and safety of recombinant
activated Factor VII in the management of refractory
traumatic hemorrhage. J Trauma 2010; 69: 489500.
Knudson MM, Cohen MJ, Reidy R, Jaeger S, Bacchetti P,
Jin C et al. Trauma, transfusions, and use of recombinant
factor VIIa: a multicenter case registry report of 380
patients from the Western Trauma Association. J Am Coll
Surg 2011; 212: 8795.
Stahel PF, Flierl MA, Moore EE. Metabolic staging after
major trauma a guide for clinical decision making? Scand J
Trauma Resusc Emerg Med 2010; 18: 34.
Pape HC, Peitzman AB, Schwab CW, Giannoudis PV
(eds). Part I: Epidemiology and Pathophysiology. In
Damage Control Management in the Polytrauma Patient.
Springer: Heidelberg, 2010; 3100.
Parr MJ, Bouillon B, Brohi K, Dutton RP, Hauser CJ,
Hess JR et al. Traumatic coagulopathy: where are the good
experimental models? J Trauma 2008; 65: 766771.
Lefering R. Development and validation of the revised
injury severity classication score for severely injured
patients. Eur J Trauma Emerg Surg 2009; 35: 437447.
Maegele M, Lefering R, Wafaisade A, Theodorou P,
Wutzler S, Fischer P et al.; Trauma Registry of Deutsche
Unfallchirurgie (TR-DGU). Revalidation
Gesellschaft fur
and update of the TASH-Score: a scoring system to predict
the probability for massive transfusion as a surrogate for
life-threatening haemorrhage after severe injury. Vox Sang
2011; 100: 231238.

www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907

Hypothermia, acidosis and coagulopathy in major injury

121 de Jongh MA, Verhofstad M, Lenen LP. Accuracy of

different survival prediction models in a trauma population.
Br J Surg 2010; 97: 18051813.
122 Vandromme MJ, Snyder CW, McGwin G Jr, Weinberg JA,
Kerby JD. A second look at the fresh frozen plasma : packed
red blood cell ratio in massive transfusion protocols. J Am
Coll Surg 2010; 210: 117; author reply 117118.
123 Valeri CR, Ragno G. Massive transfusion in patients with
severe traumatic injuries. Vox Sang 2009; 96: 180.
124 Shaz BH, Dente CJ, Harris RS, MacLeod JB, Hillyer CD.
Transfusion management of trauma patients. Anesth Analg
2009; 108: 17601768.
125 Riskin DJ, Tsai TC, Riskin L, Hernandez-Boussard T,
Purtill M, Maggio PM et al. Massive transfusion protocols:
the role of aggressive resuscitation versus product ratio in
mortality reduction. J Am Coll Surg 2009; 209: 198205.
126 Cotton BA, Au BK, Nunez TC, Gunter OL,
Robertson AM, Young PP. Predened massive transfusion

2011 British Journal of Surgery Society Ltd

Published by John Wiley & Sons Ltd

907

127

128

129

130

protocols are associated with a reduction in organ failure

and postinjury complications. J Trauma 2009; 66:
4148.
Gaarder C, Naess PA, Frischknecht Christensen E,
Hakala P, Handolin L et al. Scandinavian guidelines The
massively bleeding patient. Scand J Surg 2008; 97:
1536.
OShaughnessy DF, Atterbury C, Bolton Maggs P,
Murphy M, Thomas D, Yates S et al.; British Committee
for Standards in Haematology, Blood Transfusion Task
Force. Guidelines for the use of fresh-frozen plasma,
cryoprecipitate and cryosupernatant. Br J Haematol 2004;
126: 1128.
Stahel PF, Smith WR, Moore EE. Current trends in
resuscitation strategy for the multiply injured patient. Injury
2009; 40(Suppl 4): S27S35.
Scalea TM. Hemostatic resuscitation for acute traumatic
coagulopathy. Scand J Trauma Resusc Emerg Med 2011; 19: 2.

www.bjs.co.uk

British Journal of Surgery 2011; 98: 894907