2011 Clinical and Cellular Effects of Hypothermia Acidosis and Coagulopathy in Mayor Injury

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Review

Clinical and cellular effects of hypothermia, acidosis

and coagulopathy in major injury

K. Thorsen 1

, K. G. Ringdal3,4

, K. Strand2

, E. Søreide2,5

, J. Hagemo3

and K. Søreide1,5

Departments of 1 Surgery and 2 Anaesthesiology and Intensive Care, Stavanger University Hospital, Stavanger, 3 Department of Research, Norwegian Air

Ambulance Foundation, Drøbak, 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. Søreide, Department of Surgery, Stavanger University Hospital, PO Box 8100, N-4068 Stavanger, Norway

(e-mail: [email protected])

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 1·6–13·3 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 10–34 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 andtargeted 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 world-

wide, particularly in young people1. A main cause of

death in the first hours after trauma is bleeding. Up

to 25 per cent of all fatalities of trauma are caused by

uncontrolled haemorrhage2 – 6. Unrecognized hypoperfu-

sion from bleeding injuries has consequences for the subse-

quent development of respiratory and multiorgan failure.

The objective assessment of pending or establishedhypovolaemic shock is difficult. 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 withhypoperfusion. Hypotension as a predictor of hypo-

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 define ‘shock’8. Less than

half of all shocked patients are identified using SBP as

the sole determinant of hypoperfusion, and associated

traumatic brain injury further hampers the use of SBP asa determinant of major haemorrhage or hypoperfusion9.

Changes in vital signs with volume loss used by the

Advanced Trauma Life Support (ATLS TM

), 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

findings indicating that real life does not mirror text-

book descriptions of ‘shock’. SBP is notoriously difficult

© 2011 British Journal of Surgery Society Ltd British Journal of Surgery 2011; 98: 894–907Published by John Wiley & Sons Ltd



Hypothermia, acidosis and coagulopathy in major injury 895

to monitor and reproduce by non-invasive standards. Automated measurements often overestimate the actualblood pressure for those with true hypotension (asassessed by manual measurements)11. Recognizing thedynamic 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 mortality 12.

Uncontrolled bleeding injuries are thought to inducea ‘lethal triad of trauma’. This triad, consisting of hypothermia, acidosis and coagulopathy, is a detrimentalprognostic factor for the traumatized patient. Theimplementation of ‘damage control’ principles, duringresuscitation and surgery, has enabled better controlof these effects of trauma previously associated withhigh mortality rates13–16. A newer and more complexunderstanding 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 andcoagulopathy related to major trauma.

Methods

A PubMed/MEDLINE, Web of Science and Embasesearch was made using the search words ‘hypothermia’,

‘acidosis’, ‘coagulopathy’, ‘exsanguination’, ‘bleeding’ and‘lethal triad’ combined with ‘trauma’ and ‘injury’. Thestudy was planned by the first and last authors, whoperformed the initial literature search and manuscript draft. Further search, content revision and discussion until

agreement were performed by all authors. All authorssearched 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 focusrelating to civilian trauma were given priority for inclusion.Data from military experience or experimental studies

were included where data from civilian trauma werelacking.

Hypothermia

Post-traumatic hypothermia is either spontaneous whencaused by the accident or insult per se (such as exposure orbleeding), or therapeutic. Distinguishing between the twotypes of hypothermia is important because of the different mechanisms and effects involved. Clinical experiencefrom cardiac arrest survivors has revealed substantially better outcomes in patients with therapeutically inducedhypothermia compared with those who have spontaneous(accidental) hypothermia after resuscitation17.

Major

traumainsult

Bleeding

Tissue injury

Hypoxia

Hypotension

Hypovolaemia

Loss ofblood

Acidosis

Hypothermia

Immunology

Inflammation

Cellular responses

Molecular pathways

Mitochondria

LymphocytesThrombocytes

Pre-existing disease

Drugs and medications

Systemic

Trauma-induced

coagulopathy

Consumption of

clot factors

Fibrinolysis Dilution

Endogenous

Acute traumatic

coagulopathy

Resuscitation

Shock

Fig. 1 Complex effects leading to trauma-induced coagulopathy

© 2011 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2011; 98: 894–907Published by John Wiley & Sons Ltd



896 K. Thorsen, K. G. Ringdal, K. Strand, E. Søreide, J. Hagemo and K. Søreide

Potential benefits from hypothermia in patients withmajor trauma have been claimed using arguments drawnfrom elective surgery 18, cellular effects in experimentalstudies19, or extrapolation of the positive neurologicaleffects of clinically induced hypothermia used in cardiac

arrest 19–23. Recent findings in traumatic brain injury indicate that hypothermia may have protective effects insome patients24. In contrast to the effects and expandingrole seen in cardiac arrest survivors20,21,25, the inductionof therapeutic hypothermia after major injury remainsexperimental19,22. The following sections will thereforedeal with spontaneous hypothermia.

Definition and classification

Post-traumatic hypothermia is generally considered tobe present in patients with a body core temperature

below 35°C26–28. No uniform definition or classification

of hypothermia exists. Various cut-off values havebeen proposed19,22,28–31, although most studies refer tohypothermia as less than 35 or 36°C26,32. Accordingto the ATLS

TMdefinition, hypothermia is defined as

a core body temperature below 35°C (95°F). In theabsence of concomitant traumatic injury (also called‘accidental hypothermia’), hypothermia is classified asmild (35–32°C or 95–89·6°F), moderate (32– 30°C or89·6–86°F) or severe (below 30°C or 86°F). In injuredpatients hypothermia should be considered to be any coretemperature below 36°C (96·8°F), and severe hypothermia

is any temperature below 32°

C (89·

6°

F).Hypothermia after injury is induced by either environ-mental exposure31, the infusion of cold fluids, or as a side-effect of anaesthetic drugs affecting thermoregulation28,29.In civilian trauma, the effects of body/cavity exposure33,development of hypovolaemia and the infusion of coldfluids are the most important factors contributing to tem-perature loss.

Incidence

Accurately estimating the true occurrence of hypothermiain trauma patients is difficult because of inconsistent documentation of core body temperature34–37, variableaccuracy in measurements and inconsistent use of cut-off levels for defining hypothermia.

Large retrospective studies indicate hypothermia onadmission in 1·6–13·3 per cent of patients35,36,38–40. A large study from Pennsylvania identified 5 per cent of 38 520 trauma patients with hypothermia (defined as below 35°C)36. A study of over 700 000 trauma patients in theNational Trauma Databank in the USA found hypothermia

of less than 35°C i n 1·6 per cent and temperaturesbelow 32°C in only 802 patients (0·1 per cent)35. Anotherstudy from the same databank of 38 550 patients aged18–55 years found 8·5 per cent to have hypothermia onadmission39. 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 temperaturehomeostasis29. Responses to mild hypothermia includeincreased muscle tone and shivering, as well as metabolicincreases from the release of catecholamines and thyroxine.Below 32°C, cardiac conduction disturbances becomeapparent; atrial fibrillation is seen in about half of allpatients 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, therespiratory rate dramatically decreases and myocardialcontractility is depressed. Slowing of the heart andsupraventricular arrhythmias may give way to ventricularfibrillation and asystole18,30,41,42. Hypothermia decreasesthe enzymatic activity of clotting factors and impairsplatelet function. In addition, hypothermia inhibitsfibrinogen synthesis19,43. Anaerobic metabolism resultsin 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 thermoregulationafter injury is impaired as a resultof a lowered hypothalamictemperature threshold for the onset of shivering, whichresults 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 tothe effects of environmental exposure with increased heat loss because of radiation, conduction and evaporation fromexposed body cavities, reduced muscle perfusion lowersheat production28,44. Some authors argue that, within themost common temperature range of hypothermia seen intrauma patients (33– 36°C), isolated hypothermia probably has only a minimal clinical impact on haemostasis44.

Effects on outcome

Several studies have shown an independent relationshipbetween death and hypothermia after trauma33,35,36,38,39,

45–47. Non-survivors have a lower average body tempera-ture, higher Injury Severity Score (ISS), and an increasedblood transfusion requirement 35. The core temperaturethat has a clinical impact on trauma patients has not been





identified, but some retrospective studies have shown anindependent association with mortality in trauma patients

with an admission temperature below 35°C35,36,38. How-ever, these reports have not been consistent over time, asothers have not confirmed the association with death48,49.

Despite the association between hypothermia, shock andinjury severity, some have argued that hypothermia itself isonly a weak independent predictor of mortality 50 and that hypothermia does not contribute to the incidence or degreeof post-traumatic coagulopathy 51. Others have argued that,despite a lack of exact knowledge about the pathogenesis of post-traumatic coagulopathy, significant factors contribut-ing to its development include tissue injury, hypoperfu-sion, clotting factor dilution, hypocalcaemia, hypothermia,acidosis, inflammation and fibrinolysis27,52. Typical exper-imental 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

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 obviousindicator of metabolic acidosis in trauma is increased serumconcentration of lactate, which is produced in excessiveamounts 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 suchas 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

G o o d

P o o r

A b i l i t y

t o c o a g u l a t e

Time to haemostasis

Control

Hypothermia

Acidosis

Hypothermia + acidosis

Fig. 2 Modelling has demonstrated an additive negative effect of

factors contributing to coagulopathy

or tissue hypoperfusion. The role of metabolic acidosis inthe lethal triad is complex. It is recognized as a markerof 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 deathin exsanguinating trauma ( Figs 1 and 2).

Definitions

Acidaemia is usually considered as an arterial pH below 7·36. Acidosis refers to the pathological condition that results in acidaemia if there is no secondary compensatory response to the primary disease process. The acid–basebalance 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 deficit (referred to as base excessof less than 0). Although many factors may account forincreased values of both lactate and base excess, ongoingbleeding should be suspected until proven otherwise inpatients presenting with deranged values after trauma (suchas a base deficit of 5 or more).

The use of lactate and base deficit as markers of hypoperfusion has several limitations. Neither the causeof the metabolic acidosis nor the type of disturbanceis uniquely identified. A more specific marker would bebetter, but none is available. Tissue haemoglobin oxygensaturation is currently being explored as a non-invasive

monitor of perfusion in the trauma setting and may provideadditional data on the cause of acidosis in trauma patients56.

Bicarbonate and base deficit levels also assume nopre-existing disturbance in the non-bicarbonate buffers(haemoglobin, magnesium). In a bleeding trauma patient,these buffers are likely to be compromised, and up to50 per cent of the acid load may be caused by acids otherthan lactate57.

Albumin can influence the acid–base state, and adecrease of 1 g/dl will raise the base deficit by 3·7, whichmight lead to an acidosis not recognized by standard mea-sures. Consideration of weak acids such as phosphate andalbumin (including lactate) and arterial partial pressureof carbon dioxide have led to the development of thestrong ion difference53, originally proposed by Stewart.

This attempts to identify acid– base disorders not causedby lactate. The Stewart calculation has not yet shownany advantage over base deficit, but it can be useful indiscriminating the cause of metabolic acidosis53. Hyper-chloraemic metabolic acidosis caused by saline infusion issometimes seen in trauma patients, and base deficit doesnot identify this as well as the Stewart (or modifiedStewart)





approach57. Even though acidosis is known to induce coag-ulopathy ( Fig. 2), an in vitro study on whole blood showedthat, without the presence of hypothermia, the effect of acidosis was insignificant 58, although the blood samplestested were from healthy volunteers.


Acidosis decreases cardiac contractility, attenuates adren-ergic receptor responsiveness to inotropic agents, impairsrenal perfusion, and impairs coagulation as measured by thetime to clot and strength of the clot ( Fig. 2)59. The prop-agation phase of thrombin generation is inhibited, anddepletion of the platelet count occurs. These manifest asprolonged clotting times and increased bleeding times43.

The activity of the factor Xa/Va complex is reduced by 50 per cent at a pH of 7·2, 70 per cent at pH 7·0 and

90 per cent at pH 6·860. In addition, pH neutralizationdoes not completely correct coagulation, implying someunknown effect of acidosis60–62. These factors providestrong evidence for acidosis as a major contributor tocoagulopathy.

Effects on outcome

Outcome assessments of acidosis per se are not easy. Few studies have reported on this alone. Historical studieshave shown that the admission base deficit in addition totransfusion requirements during the first 24 h correlate

significantly with postinjury organ failure and death63

.Severe initial lactic acidosis is associated with lower cardiacperformance and higher morbidity and mortality rates64.Base excess has been reported to be the best detectorof occult hypoperfusion (defined as hypoperfusion in thepresence of normal vital signs)65. Abnormal base excessmay predict transfusion requirements, length of stay and needfor intensive care63, but is hardly ever used in isolation fordecision-making or choice of therapy. Acidosis is usually regarded as a poor prognostic sign66, although severeacidosis (pH < 6·6) has been reported with subsequent survival after trauma67.

Predictive models

Trauma score models have been developed to incorporatebase excess as a factor in the prediction of survival68–72.

The predictive ability of one such model was not superiorto that of other existing models that did not include baseexcess as a variable71. One study recently reported onthe prehospital measurement of lactate for resuscitationmonitoring, without noting any difference in outcomes73.

Another demonstrated that the time needed to normalizeserum lactate levels was an important prognostic factorfor survival in severely injured patients. All patients whoselactate levels normalized within 24 h survived, whereasonly three of 22 with persistently abnormal levels after

48 h survived74.

Coagulopathy

An understanding of coagulopathy in injured patients hasevolved with time75, notleast owing to lessons learned frommilitary experience ranging from the two World Wars torecent conflicts in Iraq and Afghanistan76.

Coagulation of blood with the formation of ahaemostatic plug is traditionally described as a cascade of events, where protein coagulationfactors, initiated throughintrinsic 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 overlappingphases, rather than in sequential steps, with an emphasison the crucial role of platelets. In the initiation phase,exposure of tissue factor-bearing cells in the vessel wall orin the circulation triggers activation of primary coagulationfactors (factors VII, X and V). The process undergoesamplification as these factors adhere to and activatethe platelet membrane. During the propagation phase,numerous factors are paired with their co-factors onthe platelet membrane, generating a burst of thrombin

production that finally converts fibrinogen to fibrin toform an interlinked fibrin clot.

Definition

Haemostasis is defined as the control of bleeding without pathological thrombotic events77. Coagulopathy can thenbe defined as any flaw in the coagulation system,leading to either increased bleeding time or increasedformation of clots. Many tests give information about coagulation status, including platelet count, prothrombintime, international normalized ratio, activated partialthromboplastin time, d-dimer and fibrinogen levels. Most

were developed half a century ago to monitor haemophiliaand anticoagulation therapy, and have not been validatedfor the prediction of haemorrhage in a clinical setting78.None is satisfactory in a trauma setting, as each takesa considerable time to measure and represents a singlepoint in a potentially ongoing process of bleeding. By thetime the test results are available, the patient may already have entered an irreversible state of hypothermia, acidosisand coagulopathy. As a result, there is growing interest





in ‘point-of-care’ testing, with capability for repeatedmeasurements and rapid results within minutes.


The simple synergy of hypothermia and acidosis ina trauma setting leading to coagulopathy has beenchallenged44,51,75,79. Rather than a secondary effect of dilu-tion and consumption as was believed in the past, trauma-induced coagulopathy (TIC) is currently considered tobe a combination of primary (endogenous response) andsecondary (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’, allof which describe the same entity 44. ATC is an impairment of haemostasis that occurs early after injury and developsendogenously in response to a combination of tissue dam-age and shock 51,80. It is associated with a fourfold highermortality rate, increased transfusion requirement and anincreased occurrence of organ failure81–83.

The incidence of TIC depends on the methodsused to measure and define the hypocoagulable orhypercoagulable state. On admission to the hospital,10– 34 per cent of trauma patients present with someform of coagulopathy 37,50,83,84. TIC can lead to both

diffuse bleeding and the formation of clots, resulting inmicrothrombosis. The condition resembles disseminatedintravascular coagulopathy (DIC), but with different initiators and underlying mechanisms44.

Mechanisms and pathways of trauma-inducedcoagulopathy

Injuries induce perturbations in the coagulation systemin many ways85. The protein C pathway seems to be animportant contributor to TIC when an injury is associated

with hypoperfusion80, consistent with findings in animalmodels86. Hypoperfusion induces expression of thrombo-modulin on the endothelial cell wall. Following thethrombin burst, thrombin combines with thrombomodulinand the endothelial protein C receptor. This complexactivates protein C, which probably plays an essential roleby inhibiting factors V, VIII and plasminogen activatorinhibitor 1, causing a hypocoagulable and hyperfibrinolyticstate ( Fig. 3). It is possible to inhibit this pathway, in thehope of reversing the state of ATC. The problem, however,is that protein C also seems to have a cytoprotectiverole strongly correlated with survival86. There may be an increased risk of developing ventilator-associatedpneumonia with low levels of protein C87. Therapeuticinhibition of this pathway is not yet possible without loss of

Injury +

hypoperfusion

Activation of platelets

Endothelial cells

Thrombin

Thrombomodulin

PC aPC

EPCR

Factor Va

Factor Va

Factor VIIIa

Factor VIIIa

Factor PAI-1

Coagulopathy

Hyperfibrinolysis

Clot formation

Activation of

FibrinFibrinogen

Fig. 3 Simple overview of the thrombin–thrombomodulin 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 hyperfibrinolytic state





the cytoprotective mechanisms, nor is selective inhibitionof the anticoagulant part of protein C.

Opponents of the concept of the protein C pathway argue that coagulopathy in trauma is simply a manifestationof DIC, with a fibrinolytic phenotype combined with

coagulation factor depletion88. Further, they point out that any state of serious systemic hypoperfusion inducesexcessive fibrinolysis 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 insufficient platelet levels. Thrombocytopenia at admission after

trauma has been linked to increased mortality, and thehighest survival rates are seen in patients receiving thehighest platelet to erythrocyte ratio of transfusion89.

Although platelet counts and outcome do correlate, littleis known about the potential mechanisms behind this

association. Function is probably more important than theabsolute platelet count. Platelet function is to some extent reflected by viscoelastic haemostatic assays (VHAs) such asthromboelastography (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 hasnot been investigated thoroughly in the trauma setting90.

The cell-based model of coagulation emphasizes the

role of platelets in fibrin formation through the cascadeof events taking place on the thrombocyte membrane.Platelets are probably the most important factors involvedin coagulation. Despite this, the role of platelets in

TIC is poorly investigated and management guidelinesare ambiguous81,91. Yet, the trend in massive transfusionprotocols worldwide has been towards the early additionof platelets in a ratio approaching 1 : 1 : 1 for packed redblood cells to fresh frozen plasma to thrombocytes92–94.

Fibrinogen levels, the formation of fibrin and trauma-

induced fibrinolysis have been central in the investigationof traumatic coagulopathy 43,61,95. Primary fibrinolysisappears to be fundamental in TIC and occurs early (less than 1 h) after trauma. Fibrinolysis is associated

with massive transfusion requirements, coagulopathy andhaemorrhage-related death96. Trauma alters fibrinogen

metabolism in a variety of ways43. Ongoing haemorrhagemay cause accelerated fibrinogen breakdown. Loss of bloodand decreases in core body temperature inhibit fibrinogensynthesis, and acidosis causes accelerated fibrinogen

breakdown. Haemorrhage, hypothermia and acidosis allresult in reduced availability of fibrinogen, supporting the

notion of fibrinogen supplementation in trauma patients with coagulation defects43,62. In this regard, point-of-care testing with thromboelastography seems crucial inidentifying coagulation abnormalities at an early stage.

When evaluating whole blood in the fluid phase after

a traumatic insult, there is research that suggests anassociation between coagulopathy and ISS. A near linearrelationship has been shown to exist between the degreeof coagulopathy and increasing ISS83. This associationis even stronger when adding hypothermia, acidosis andhypotension to severity of injury 97.

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 diag-

nostic tools52,78,90

. Rapid thromboelastography (thrombo-elastography with added tissue factor) is an alternative,together with several other modifications for this technol-ogy. The most widely explored and used technologies are

TEG ® and ROTEM®78. These instruments measure andreproduce the phenomenon of clotting in graphical and/ornumerical format ( Figs 4 and 5 ).

The advantages of VHAs are many, and includeevaluation of the coagulation system in whole blood. Theendpoint is clinically relevant, that is clotting in wholeblood (fibrin formation, clot retraction and fibrinolysis).

The results are available quickly (in about 20 min for rapid

TEG®

ROTEM®

R

CT

K

CFT

αMA

MCF

Ly

CL

Time Kinetics Strength Lysis

Coagulation Fibrinolysis

Fig. 4 Clotting evaluation by thromboelastography (TEG ®).Schematic trace indicating the commonly reported variables

reaction time (R)/clotting time (CT), clot formation time (K,

CFT), angle α, maximum amplitude (MA)/maximum clot

firmness (MCF) and lysis (Ly)/clot lysis (CL). Examples for

reading include TEG ® (upper part) and rotational

thromboelastometry (ROTEM®) (lower part). With slight modifications and reproduced with permission from Johansson

et al .78





Rmin6·2

2 – 8

Kmin1·9

1 – 3

Angledegrees

62·755 – 78

MAmm61·1

51 – 69

Gd/sc7·9K

4·6K – 10·9K

Amm55·5

EPL%

0·70 – 15

LY30%

0·70 – 8

−0·3−3 – 3

CIPMA

0·0

Rmin6·4

2 – 8

Kmin1·7

1 – 3

Angledegrees

65·655 – 78

MAmm25·6

51 – 69

Gd/sc1·7K

4·6K – 10·9K

Amm0·7

EPL%

∗97·4∗

0 – 15

LY30%

∗92·3∗

0 – 8−4·5−3 – 3

CIPMA

0·0

Rmin20·12 – 8

Kmin10·61 – 3

Angledegrees

20·055 – 78

MAmm45·1

51 – 69

Gd/sc4·1K

4·6K – 10·9K

Amm43·5

EPL%

∗3·5∗

0 – 15

LY30%

∗0·7∗

0 – 8−17·8−3 – 3

CIPMA

1·0

10 mm

10 mm

10 mm

a Normal

b Hyperfibrinolysis

c Hypocoagulable

Fig. 5 Examples of thromboelastography readings: a normal clotting status, b hyperfibrinolysis and c hypocoagulable state. R, reaction

time (period of latency between placing blood sample in analyser and initial fibrin formation); K, clot kinetics (clot formation time, or a

measure of the time to reach a specific level of clot strength); MA, maximum amplitude; G, measure of clot strength (a direct function

of the maximum dynamic properties of fibrin and platelet bonding via GPIIb/IIIa representing the ultimate strength of the fibrin clot);CI, coagulation index (a linear combination of clot time, clot kinetics and clot strength); LY30, fibrinolytic profile (measures the rate of

amplitude reduction 30 min after MA)





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 andliver surgery 78. 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. VHAscannot detect the effects on platelet function related to

commonly used drugs such as clopidogrel, non-steroidalanti-inflammatory drugs and aspirin. As the assay is usually performed at a constant temperature of 37°C (although it may be calibrated to the patient’s actual temperature),

the effect of hypothermia is not recognized in thissystem.

Implications for fluid therapy

Blood component therapy, or ‘haemostatic damagecontrol resuscitation’13,100–103, has received renewedinterest after favourable reports in military situations.Outcomes in civilian trauma have been conflicting so

far104–106 . Although a ratio of 1 : 1 for packed redcells to plasma (and platelets) seems to be widely supported93,107, there is no firm evidence for this in civiliantrauma92,104,108–111. On the contrary, this protocol hasbeen shown to be harmful when administered to the wrong

patients112, with an increase in complications and organdysfunction.

Recent trials have investigated the effects of otheradditions during resuscitation. A randomized study

of over 20000 patients compared tranexamic acid(an antifibrinolytic agent) with placebo for correctionof fibrinolysis. There was a reduction in both all-cause 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, Bagsværd, Denmark)reduced the amount of blood product used compared withplacebo, but did not affect mortality. The generalizability

of these studies is hampered by their design (selectionof study population, study centres, accrual of patients,

level and expertise of provider care, lack of standardizedmeasurements, criteria for presence or severity of coagulopathy). A recent multicentre study found activatedfactor VII to be of l ittle or no use in patients

with sustained shock, acidosis and a low platelet count 115.

Goal-directed therapy to correct coagulopathy after

trauma seems warranted in selected patients, but the best choice of agent is still not known.

Discussion

The human response to trauma, involving a complex

of physiological, biochemical, immunological and cel-

lular mechanisms, may be unpredictable116. Protracted

reduction in tissue perfusion after major trauma producesprofound effects on tissue metabolism, structure and func-tion 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 touse and interpret in prognostication and decision-making

can then follow. In turn, this leads to more logical timingand composition of fluids 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 fluid83. 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 shock 118.

The inclusion of hypothermia, acidosis and coagulopa-

thy in formal scores for outcome prediction has not been

widely entertained, but could be useful if available through

bedside measurements. Some recently developed scoringtools 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 Classification 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, diffi-cult to handle and associated with increased mortality 82.

A number of institutional, societal and regionalguidelines27,94,101,107,122–129 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 find reliable tests that

quickly identify these patients. They often make heavy

demands on transfusion services in terms of requirementsfor blood and its components that cannot always be met.





It follows that there is an equally important need to devisetherapies 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 addfurther to benefits derived from blood component therapy for severely injured patients when appropriate diagnostic

tools are available in the future.

Acknowledgements

The authors declare no conflict of interest.

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2011 Clinical and Cellular Effects of Hypothermia Acidosis and Coagulopathy in Mayor Injury

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