Review Clinical and translational aspects of hypothermia in major trauma patients: From pathophysiology to prevention, prognosis and potential preservation Kjetil Søreide a,b,c, * a Department of Surgery, Stavanger University Hospital, Stavanger, Norway b Institute of Health and Medicine, University of Stavanger, Stavanger, Norway c Department of Clinical Medicine, University of Bergen, Bergen, Norway Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647 Definition, measurements and classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648 Aetiology for hypothermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649 Prevalence of hypothermia after trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649 Physiologic effects of trauma-induced hypothermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650 Prognostic implications of trauma-induced hypothermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650 Prevention/prophylaxis and treatment and of hypothermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651 Prophylactic and therapeutically induced hypothermia in trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652 Neuroprotective effect in TBI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652 Hypothermia as a preserving mechanism in multisystem trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652 Introduction The human body strives at maintaining homeostasis within fairly tight regulated mechanisms that control vital regulators such as core body temperature, mechanisms of metabolism and endocrine functions. These essential functions may demonstrate Injury, Int. J. Care Injured 45 (2014) 647–654 A R T I C L E I N F O Article history: Accepted 28 December 2012 Keywords: Hypothermia Injury Organ failure Mortality Prevention Prevalence A B S T R A C T The human body strives at maintaining homeostasis within fairly tight regulated mechanisms that control vital regulators such as core body temperature, mechanisms of metabolism and endocrine function. While a wide range of medical conditions can influence thermoregulation the most common source of temperature loss in trauma patients includes: exposure (environmental, as well as cavitary), the administration of i.v. fluids, and anaesthesia/loss of shivering mechanisms, and blood loss per se. Loss of temperature can be classified either according to the aetiology (i.e. accidental/spontaneous versus trauma/haemorrhage-induced temperature loss), or according to an unintended, accidental induction in contrast to a medically intended therapeutic hypothermia. Hypothermia occurs infrequently (prevalence < 10% of all injured), but more often (30–50%) in the severely injured. Hypothermia usually come together with and may aggravate acidosis and coagulopathy (the ‘‘lethal triad of trauma’’), which again may be associated with a high mortality. However, recent studies disagree in the independent predictive role of hypothermia and mortality. Prevention of hypothermia is imperative through all phases of trauma care and must be an interest among all team members. Hypothermia in the trauma setting has attracted focus in the past from a pathophysiological, preventive and prognostic perspective; yet recent focus has shifted towards the potential for using hypothermia for pre-emptive and cellular protective purposes. This paper gives a brief update on some of the clinically relevant aspects of hypothermia in the injured patient. ß 2013 Elsevier Ltd. All rights reserved. * Corresponding author at: Department of Surgery, Stavanger University Hospital, POB 8100, Armauer Hansens vei 7, N-4068 Stavanger, Norway. Tel.: +47 5151 8330; fax: +47 5151 9919. E-mail address: [email protected]. Contents lists available at SciVerse ScienceDirect Injury jo ur n al ho m epag e: ww w.els evier .c om /lo cat e/inju r y 0020–1383/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.injury.2012.12.027
Transcript
Injury, Int. J. Care Injured 45 (2014) 647–654
Review
Clinical and translational aspects of hypothermia in major trauma patients:From pathophysiology to prevention, prognosis and potential preservation
Kjetil Søreide a,b,c,*a Department of Surgery, Stavanger University Hospital, Stavanger, Norwayb Institute of Health and Medicine, University of Stavanger, Stavanger, Norwayc Department of Clinical Medicine, University of Bergen, Bergen, Norway
0020–1383/$ – see front matter � 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.injury.2012.12.027
Introduction
The human body strives at maintaining homeostasis withinfairly tight regulated mechanisms that control vital regulators suchas core body temperature, mechanisms of metabolism andendocrine functions. These essential functions may demonstrate
Fig. 1. Schematic depiction of thermoregulation. The hypothalamus works as the central thermoregulator and reacts upon a stimulus (i.e. cold) by a response (i.e. muscle
shivering) to increase the temperature. When normothermia is reached a negative feedback loop regulates the stimulus so as not to overgenerate heat. The response may be
blunted, e.g. in an unconscious patient or a patient receiving neuromuscular blockade during anaesthesia.
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just slight circadian oscillation under normal circumstances,1 suchas temperature oscillation maintained between 2 and 48C on acircadian basis. Regulation of temperature follows through astimulus–feedback system that ensures either generation of heat(through muscle shivering) if temperature falls, or the removal ofexcess heat through generation of sweat and vasodilation (seemechanisms in Fig. 1). However, any disruption of the homeostaticmechanisms may blunt these otherwise tightly controlledmechanisms (e.g. bacterial infection leading to fever; or loss ofconsciousness leading to heat loss and failure to compensatethrough shivering). A major trauma insult on the human body istypically followed by deregulated mechanisms ranging fromcellular and molecular mechanisms,2 to altered human physiologyand single or multi-organ dysfunction. For severely injuredbleeding patients the extreme form may be characterised as the‘‘lethal triad of trauma’’ with acidosis, hypothermia and coagulo-pathy with a very high mortality even in the modern era of traumamanagement.3 Hypothermia in the trauma setting has attractedinterest in the past from a pathophysiological, preventive andprognostic perspective, yet recent focus has shifted towards thepotential for using hypothermia for pre-emptive and cellularprotective purposes. This review gives an overview on currentfindings and results reported for hypothermia in trauma victims.
Definition, measurements and classification
Hypothermia is usually considered to be present in traumapatients with a body core temperature < 35 8C. However, as noglobally agreed classification of hypothermia exists, various cut-offvalues have been used for the definition of hypothermia, but moststudies refer to hypothermia as either <35 8C or �35 8C.4–9 In 2008,the ATLS redefined hypothermia parameters for trauma – forinjured patients it is now <36 8C – for patients exposed such as insubmersion injury, it remains <35 8C.
Notably, while recording body temperature is perceived as aneveryday procedure and one of the most used ways of evaluatingthe general health condition, it may be associated with aconsiderable larger uncertainty than probably perceived by mostclinicians. Temperature can be measured and monitored either byinvasive means (by a pulmonary catheter, by probes in theoesophagus or bladder or by rectal probes) or by non-invasivetechniques (oral, axillary, temporal artery and ear-based measure-ments). A number of factors may influence temperature measure-ments and interpretation, including human factors such as patientsage and gender,10–12 choice of technique and location, measure-ment errors on the side of the user, or equipment errors based ontechnical or calibration issues.10,12–14 Considerable variation existsin measurement accuracy, but pulmonary artery measurementsand rectal temperature appears to be fairly accurate anddemonstrating good correlation for estimating core body temper-ature, usually with as little as �0.1 8C in variation.11,15,16 Probesinserted in the urinary bladder may also be an alternative, withtemporal artery reading and axillary measurements being lessreliable – with up to �1 8C in difference from invasively recordedmeasurements – although widely used in clinical practice. As noveland improved techniques develop it is hoped that more standardisedand reliable measurements can be obtained.13
Loss of temperature can be classified either according to theaetiology (i.e. accidental/spontaneous versus trauma-induced), orthe mode of induction, such as an accidental drop of temperaturein contrast to that of a medically intended use of therapeutichypothermia. Usually one would consider hypothermia as eitherspontaneous or accidental when caused by an accident or insult perse (such as cold exposure) or therapeutic when used as atherapeutic means. While trauma-induced hypothermia mayinclude an accidental component (exposure to cold weather) itis important to make clinical distinction between isolatedaccidental/spontaneous hypothermia and that of trauma-induced
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hypothermia, as the accidental hypothermia has much betteroutcome, should receive prolonged resuscitation until core bodytemperature has been achieved, and as long- and short-termsurvivors have been described at extreme temperatures below20 8C,17,18 with lowest core body temperature recorded at13.7 8C.18 Notably, trauma patients do worse within both extremesof body temperature ranges, both in civilian and military injuries.19
Aetiology for hypothermia
Multiple factors may contribute to loss of temperature after aninjury insult, and across all phases of trauma care (Fig. 2). Ingeneral, hypothermia after injury is induced either by environ-mental exposure,20 by the infusion of cold intravenous fluids, as aconsequence of haemorrhagic shock or as a side effect ofanaesthetic drugs affecting thermoregulation.6,21 One study of aphysician-manned pre-hospital emergency service in London22
found a significant difference in body temperature betweenanaesthetised patients (n = 207) and non-anaesthetised patients(n = 287) for a difference in temperature (mean � SD 35.0 � 2.1 8Cvs. 36.2 � 1.0 8C, respectively; p < 0.001). This is in line with a recentpre-hospital, multicentre observational study that found 15% oftrauma patients to be hypothermic, with severity of injury,environmental conditions and the medical care provided by EMSas significant risk factors for hypothermia.23
In-hospital factors may further aggravate loss of temperature;cavitary exposure during surgery should be noted as a source fortemperature loss and associated mortality.7 Inaba et al.7 found thatwhen compared to patients with normal temperature at the end ofan operation, hypothermic patients had a significantly highermortality (35% versus 8%; p < 0.001). With decreasing tempera-tures, there was a stepwise increase in mortality, and mortalitywas an independent predictor of mortality adjusted for othervariables in this study. However, they did not report on the numberof patients that were hypothermic before entering the operatingroom and stayed hypothermic; or the numbers who became
Fig. 2. Sources of temperature loss
hypothermic due to exposure in the operating room. Nonetheless,the dangers of temperature loss during surgery should be kept inmind.
A wide range of medical conditions can also influencethermoregulation. However, in civilian trauma, exposure, hypo-volaemia and the infusion of cold fluids are likely the mostimportant factors contributing to temperature loss in an injuredindividual. Notably, while studies have found no seasonaldifference in the occurrence of hypothermia,9,22,24,25 others havefound a positive association to winter time.26 Precautions shouldbe taken during all seasons to prevent the further loss oftemperature in the injured patient.
Prevalence of hypothermia after trauma
Accurately estimating the true occurrence of hypothermia intrauma patients is difficult because of inconsistent documentationof body core temperature,3,19,27–30 lack of a reference standard tomeasure body temperature, reported variable accuracy in mea-surement tools and inconsistent use of cut-off levels for defininghypothermia. However, many studies appear to agree on a bodycore temperature of �35 8C as clinically relevant and as animportant cut-off for hypothermia.4–6,8,9,28
The incidence of post-traumatic hypothermia has beeninvestigated in a number of larger retrospective studies indicatingthat the prevalence of hypothermia on admission varies from 1 to10% of all injured patients3,5,9,19,23,27,28,30 while not adjusted forinjury severity. Indeed, hypothermia may be as common as everythird severely injured (ISS � 16) adult trauma patient.31 Largerdatabase studies from the United States have found 5–9% of traumapatients to be hypothermic (defined as <35 8C).5,28 A NationalTrauma Databank (NTDB) study in >700,000 trauma patientsfound hypothermia in 1.6% of patients, with temperatures < 32 8Cin only 802 patients (0.11%).27 The data mentioned aboveunderscore that prevalence changes with the groups studied (withage-groups included/excluded; dependant on injury severity and,
during trauma management.
Fig. 3. Symptoms associated with decrease in body temperature. Considerable overlap in clinical effect for each decrease in temperature exists from person to person, and is
dependent on several aspects, including the age and general health of the patient; medications taken/given; other drugs and alcohol; as well as type and severity of injury.
However, the illustrations serves to demonstrate the increase in deranged physiology that follows the extent of temperature loss.
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the type of injuries) and, that hypothermia is not common intrauma patients overall, but might have detrimental effects in themost severely injured, e.g. ISS > 15 and higher.24
Physiologic effects of trauma-induced hypothermia
Mild heat loss is usually well-tolerated with compensatorypathophysiological changes to maintain temperature homeosta-sis.6 Responses to mild hypothermia include increased muscle toneand shivering (Fig. 1), as well as metabolic increases from therelease of catecholamines and thyroxin. Below 32 8C, cardiacconduction disturbances become apparent; atrial fibrillation is notuncommon with core temperatures below 30 8C (Fig. 3). Notably,there is no artificial cut-off temperature where one event may ormay not occur over another. Obviously the effects of hypothermiamay be influenced by many factors, including other sustainedinjuries and the patient’s age and comorbidity. Fig. 3 gives anillustrative view of the potential danger areas when temperaturedecrease may lead to deranged physiological function. Below 28 8C,serious abnormal cardiac rhythms may occur. Below 28 8C,respiratory rates decrease and may stop, myocardial contractilityis depressed, and the initial slowing of the heart and supraven-tricular arrhythmias may give way to ventricular fibrillation and,finally, asystole.32–35 Hypothermia decreases the enzymaticactivity of clotting factors and impairs platelet function (Fig. 4).In addition, hypothermia inhibits fibrinogen synthesis.36,37 Trau-ma-induced shock results in anaerobic metabolism that can giveway to reduced adenosine triphosphate (ATP) synthesis, resultingin the decreased hydrolysis of ATP to adenosine diphosphate (ADP)and hence decreased heat production.36 Previous data from animalresearch have shown that thermoregulation after injury isimpaired as a result of a lowered hypothalamic temperaturethreshold for the onset of shivering, which results in either noshivering, or only slight shivering, observed at about 31 8C.
Similarly, an impairment in the threshold for vasoconstrictionmay also occur after trauma. In addition to the effects ofenvironmental exposure, trauma patients have reduced heatproduction due to low perfusion of the muscles and mayexperience increased heat loss because of radiation, conductionand evaporation from exposed body cavities if subject tosurgery.21,38 Some authors have argued that within the mostcommon temperature range of hypothermia seen in traumapatients (33–36 8C), isolated hypothermia probably has only aminimal clinical impact on haemostasis.38 Nonetheless, all meansto prevent temperature loss should be introduced early on from theprehospital phase to reception in the emergency room.
Prognostic implications of trauma-induced hypothermia
Several past and current retrospective studies have shown anindependent relationship between mortality and hypothermiaafter trauma,5,7,9,27,28,39–41 with non-survivors demonstrating alower average body temperature, higher ISS, and an increasedblood transfusion requirement. Some retrospective studies haveshown an independent association with mortality in traumapatients with admission temperatures < 35 8C.9,26,27,28 Further,two recent publications from the Los Angeles area demonstratedan increased mortality in patients with TBI who had hypothermiaon admission or the pre-hospital phase, suggesting this as anindependent prognostics factor.42,43 However, results have notbeen consistent over time, as others have not confirmed theassociation with mortality.8,30,31,44 A recent large German study of>5000 patients did not find an independent predictive effect ofhypothermia on mortality,30 rather it suggested that hypothermiais part of the detrimental physiological effects that come withsevere injury and haemorrhage (and thus acidosis and coagulo-pathy). A more recent association between hypothermia andincreased organ dysfunction, but not mortality,8 may indeed point
Fig. 4. Pathophysiological effects of hypothermia in several organ systems.
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to several factors; an increased awareness of hypothermia; betterprevention to ameliorate further heat loss; but, also to the generaladvancement in critical care for the most severely wounded. Assuch, recent studies have proposed that hypothermia has noindependent effect on mortality in different models, and likelymortality prediction was reflected in the co-existence of acidosisand coagulopathy.30,45,46
Hypothermia may contribute to increased morbidity, includinghigher risk for organ dysfunction8 and as a risk-factor for surgicalsite infection in trauma laparotomies.4 Again, awareness anddiligent screening for the current body temperature in injuredpatients is mandatory to detect, prevent and treat furthertemperature loss.47 This is important among all team membersand needs attention alike other important tasks in the early work-up and management of the trauma patient.
Prevention/prophylaxis and treatment and of hypothermia
Prevention and treatment of hypothermia are often two of akind – however, emphasis should be prevention firstly andtreatment with further prevention once hypothermia has beendiagnosed by screening the temperature. Modalities may rangefrom simple, non-invasive, passive external warming techniques(such as, removal of cold, wet clothing; movement to a warmenvironment) to active external rewarming (e.g. insulation withwarm blankets) to active core rewarming (e.g. warmed intrave-nous fluid infusions, heated humidified oxygen, body cavity lavage,and extracorporeal blood warming).
Only one randomised trial has been performed for activetreatment to correct hypothermia.41 In the trial, no effect wasdemonstrated for survival, but those receiving standard rewarm-ing (compared to invasive rewarming) had higher fluid require-ments during the intensive care phase. There is considerable costsand use of resources needed to actively rewarm hypothermictrauma-patients with the latter technique, knowingly with nodemonstrable clinical effect on outcome.
The proclamation ‘‘prevention is the best treatment’’ holds truealso for hypothermia. Prevention of heat loss is usually easy toperform (in most cases), yet likely the most commonly forgottenmeasure in the care of the injured. Even in a major trauma centre inLondon the body temperature was only recorded in 38% of alltrauma patients on admission.22 ‘‘If you don’t take a temperatureyou wont find a fever’’ – likewise goes the saying for hypothermiaand temperature loss undetected if temperature is not measured.Missing values of temperature is fairly frequent in reports fromtrauma databases, and a recently proposed collection of commoncore data points in trauma victims did not include temperature as acore variable.48 In light of the association with hypothermia andmortality, the lack of temperature as a core variable may be viewedas a failure. However, recent modelling of prognosis does notsupport hypothermia as a core variable.30 Be it right or wrong, thisdecision was derived from the consensus agreement among a largenumber of international researchers.49,50 It may be subject tofuture revisions.
Preventive measures should start in the pre-hospital phasefor all trauma victims (Fig. 2). One study of healthy volunteers,showed that a combination of vapour tight layer and anadditional dry insulating layer (called Hibler’s method) wasthe most efficient wrapping method to prevent heat loss, asshown by increased skin temperatures, lower metabolic rate andbetter thermal comfort.51 A small, randomised trial fromnorthern Sweden demonstrated that in patients with mildhypothermia after trauma and a preserved shivering capacity,passive warming was effective in establishing a slow rewarmingrate and in reducing cold discomfort during prehospitaltransportation.52 However, the addition of active warmingusing a chemical heat pad applied to the torso significantlyimproved thermal comfort and could potentially reduce the coldinduced stress response. Obviously, awareness of cold exposurethroughout all links in the ‘trauma chain of survival’ is crucial,53
and education and protocols for the entire team involved isessential.26,54
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Prophylactic and therapeutically induced hypothermia in trauma
Clinical experience of therapeutic hypothermia from cardiacarrest, stroke and newborn asphyxia have revealed prognosticdifference in outcomes, with improved outcomes overall and forneurologic recovery with induced hypothermia under controlledconditions. Further, potential benefits from hypothermia havebeen suggested from elective surgery,34 and extrapolated fromcellular effects demonstrated in in vitro studies.36 Extrapolation ofthe positive effects of clinically-induced therapeutic hypothermiaused in cardiac arrest on the improved neurologic outcome55 haveprobably been most convincing, particularly for isolated injuries ofthe central nervous system. Additionally, recent findings intraumatic brain injury seem to indicate that hypothermia mayhave protective effects in selected victims.56,57 However, incontrast to the effects and expanding role seen in cardiac arrestsurvivors,55,58–60 the induction of therapeutic hypothermia aftermajor injury remains a largely experimental option.36,61 Notably,controversies still persist in indications, initiation and depth ofhypothermia for cardiac arrest.62 Recent reviews have explored thetechnical details concerning methods of inducing hypother-mia,63,64 which are beyond the scope of this review.
Neuroprotective effect in TBI
The majority of evidence of the neuroprotective effects of mildto moderately induced hypothermia stem from animal research,the clinical role is as of yet undefined and human studies areneeded for better clarification of the actual therapeutic effect.65
Two recent North American studies demonstrated a detrimentaloutcome in (non-therapeutic induced, accidental) hypothermiaand traumatic brain injury (TBI).42,43
The neuroprotective effects of therapeutic hypothermia inisolated types of injuries, most often TBI or spinal cord injuries(SCI), have currently revealed conflicting results in clinicaltrials.65,66 For TBI studies, the conflicting results are partlyexplained by different trial designs used by the investigators.Roughly, studies of hypothermia for patients with severe braininjury can be divided into either studies of hypothermia used totreat raised intracranial pressure or, studies were hypothermia isintended as a neuroprotective intervention to stop the biochemi-cal/inflammatory cascade after injury.67 Thus, immediate compar-ison of studies may be difficult and unwarranted. Further,underpowered studies and dubious subgroup analyses havecontributed to the controversy in the past. However, larger clinicalstudies are underway. More recently, the randomised clinical trial‘National Acute Brain Injury Study: Hypothermia II’ (NABIS II trial)failed to demonstrate any beneficial effect of early introduction ofmild hypothermia in patients with TBI.68 However, the study hasbeen criticised among others for rewarming patients too early,which may have led to increased intracranial pressures and worseoutcomes.69 Two ongoing trials may give additional answers onthe therapeutic effect of hypothermia in patients with TBI. One isthe European trial ‘EUROTHERM’ (Current Controlled TrialsISRCTN34555414) which aim for 1800 patients and is stillrecruiting with recruitment to be stopped in 2013.70 TheEUROTHERM trial is a pragmatic, multi-centre RCT examiningthe effects of hypothermia at 32–35 8C and titrated to reduceintracranial pressure < 20 mmHg. Outcome will be examined onmorbidity and mortality at 6 months after TBI. Further, a RCTinitiated by the Australian and New Zealand Intensive Care ClinicalTrials Group (ANZICS-CTG) named POLAR (Prophylactic Hypother-mia Trial to Lessen Traumatic Brain Injury; Clinicaltrials.govNCT00987688) is currently also recruiting patients and isestimated to complete recruitment by late 2013. Hopefully, theEUROTHERM and POLAR studies will cast new light on thepotential benefit of hypothermia in TBI.
Hypothermia as a preserving mechanism in multisystem trauma
For multisystem trauma or severe exsanguinating injuries theinduction of hypothermia is thought of as part of an earlyapplication of novel cell protective strategies to allow time forsurgical repair that would otherwise take too much time (causingsevere ischaemic injury to the brain and the heart) or be associatedwith detrimental effects of resuscitation, including ischaemia–reperfusion sequela and organ injury and dysfunction.36,71 Thisexciting principle has yet to be brought to fruition from thelaboratory and into clinical practice, but could break barriers andimprove outcomes for patients otherwise unsalvageable withcurrent methods.
For multisystem trauma, the clinical experience of inducedhypothermia is very limited, with only a case series of six patientsreported with intended therapy-induced hypothermia for severeinjuries suffering cardiac arrest.72 However, an abundance ofanimal research and evolving understanding of basic mechanismsare unfolding. From several animal experiments,10,13,14,70,73–76 itappears that cellular preservation mechanisms can be inducedwith therapeutic hypothermia. Notably some of these definitionsare outside the range currently applicable for clinical use (i.e. deep,profound and ultra-profound hypothermia) as therapeutic hypo-thermia are classified into mild (33–36 8C), moderate (28–32 8C),deep (16–27 8C), profound (6–15 8C), and ultra-profound (<5 8C).36
The mechanisms and approach to induce a rapid total bodypreservation, to allow for repair of injuries during metabolic arrest,then followed by controlled resuscitation defines the concept of‘emergency preservation and resuscitation’ (EPR), recentlyreviewed in detail elsewhere.71 Extensive preclinical data suggestthat in advanced stages of shock, rapid cooling can protect cellsduring ischaemia and reperfusion, decrease organ damage, andimprove survival.36,61 However, it should be noted that inductionof hypothermia is a double-edged sword. The practical applicationof therapeutic hypothermia is not trivial, and the treatment carriesrisks. Unless managed carefully, its induction can be associatedwith a number of complications.36,61,63,71 However, if thelaboratory success of the groups working on therapeutic andmechanistic understanding of this can bring the knowledge for asafe transfer to the bedside, it may pose a considerable advanceforward for severely injured patient having otherwise a poorchance of good outcome.
Conflict of interest statement
The authors have no conflicts of interests to declare related tothe content or publication of this manuscript.
Acknowledgements
The paper is in part based on a lecture ‘‘Hypothermia andacidosis in trauma’’ held for the Masters in Trauma Sciences courseby the Barts and the London School of Medicine, Queen MaryUniversity of London; and the Royal College of Surgeons ofEngland, in 2011.
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