TY - JOUR AU - Alam, H B AB - Abstract Background Hypothermia is commonly used for organ and tissue preservation in multiple clinical settings, but its role in the management of injured patients remains controversial. There is no doubt that temperature modulation is a powerful tool, and hypothermia has been shown to protect cells during ischaemia and reperfusion, decrease organ damage and improve survival. Yet hypothermia is a double-edged sword: unless carefully managed, its induction can be associated with a number of complications. Methods A literature review was performed to include important papers that address the impact of hypothermia on key biological processes, and explore the potential therapeutic role of hypothermia in trauma/haemorrhage models. Results No clinical studies have been conducted to test the therapeutic benefits of hypothermia in injured patients. However, numerous well designed animal studies support this concept. Despite excellent preclinical data, there are several potential barriers to translating hypothermia into clinical practice. Conclusion Therapeutic hypothermia is a promising life-saving strategy. Appropriate patient selection requires a thorough understanding of how temperature modulation affects various biological mechanisms. Introduction Deaths resulting from injuries are acute1–4, with about half occurring before arrival to hospital. Massive blood loss and central nervous system (CNS) damage are the main causes of death. Compared with severe CNS damage, deaths due to bleeding are potentially preventable with early control of bleeding and adequate resuscitation. Despite numerous advances in trauma care5, the majority of deaths still occur within the first few hours following injury. Clearly, to make a difference in outcomes, efforts should focus on providing more effective early trauma care. After severe trauma, patients typically have worsening hypotension (prearrest phase) before full cardiopulmonary arrest. Hypotension (systolic blood pressure less than 90 mmHg) is predictive of very high mortality risk (54 per cent) after trauma6, and absence of a palpable pulse is associated with almost certain death unless the source of haemorrhage can be controlled within minutes7. Recognition of this rapid progression from shock to death has led to a widespread policy of urgent operative intervention in patients who are in shock. It is well recognized that typical cardiopulmonary resuscitation strategies, such as chest compression and forced ventilation, are ineffective in this setting8,9. Similarly, intravenous fluid resuscitation in these patients, before control of haemorrhage, is not only ineffective but may even be harmful10,11. Owing to the futility of these measures, expeditious transport to specialized trauma centres (scoop and run) has been the mainstay of prehospital trauma care in the USA since the mid-1980s12. To avoid complications of aggressive fluid resuscitation, an idea that has recently gained popularity is haemostatic/damage control resuscitation13. The basic tenets of damage control resuscitation are: avoid crystalloid resuscitation; aim for permissive hypotension whenever possible; and prevent coagulopathy by early use of blood products. The overarching goal of this approach is to serve as a bridge to definitive measures (such as surgical haemorrhage control). Once the injured patient gets to hospital, aggressive surgical procedures such as emergency department thoracotomy are often performed for haemorrhage control14, but very few patients survive (approximately 7 per cent for penetrating and less than 1 per cent for blunt trauma)15. On autopsy, a significant number of these patients are found to have potentially repairable injuries that could not be controlled before the onset of irreversible shock. Once the patient becomes pulseless, the window of opportunity is very brief as the critical warm ischaemia time is only 5 min for the brain16,17, and about 20 min for the heart18. This is clearly not enough time to perform any complex surgical manoeuvres and, not uncommonly, even if haemorrhage is controlled and spontaneous circulation restored, patients are left with severe neurological deficits. Similarly, many patients who survive the initial surgery often succumb to reperfusion injury, septic complications, and multiple organ failure after surgery. As these patients consume a lot of resources the cost to the healthcare system is extremely high. With all the recent advances in medicine, one question is whether early application of novel cell protective strategies could save these lives. Theoretically, early initiation of treatment that makes tissues more resistant to ischaemia could provide valuable additional time for the surgeons to address life-threatening injuries. This time could also be used to transport the patient to an operating room for definitive repair of injuries and, theoretically, even to another treatment facility. Finally, appropriate resuscitation could be performed in a systematic fashion once the source of bleeding is controlled. This approach of rapid total body preservation, repair of injuries during metabolic arrest, followed by controlled resuscitation defines the concept of emergency preservation and resuscitation (EPR). Role of hypothermia in emergency preservation and resuscitation Although rapid haemorrhage control followed by adequate resuscitation remains a cornerstone of modern trauma care, it is not as simple as refilling an empty tank. At the cellular level, haemorrhage and resuscitation induce changes that are very similar to ischaemia–reperfusion injury, including the production of reactive oxygen species, activation of the inflammatory cascade, and increased apoptotic cell death19–21. Thus, innovative strategies for the management of a patient with bleeding and multisystem trauma must also consider cellular protection as a means of minimizing organ damage. Currently, hypothermia is the most effective method for preserving cellular viability during ischaemia and reperfusion. There is no strictly accepted nomenclature by which to define the depth of clinically induced therapeutic hypothermia. As the physiological response of tissues to hypothermia varies according to its temperature, it is important to stratify the current literature correspondingly. For the purposes of this review the depth of therapeutic hypothermia is classified as: mild (33–36 °C), moderate (28–32 °C), deep (16–27 °C), profound (6–15 °C) and ultraprofound (5 °C or less). The potential benefits of hypothermia have been known for decades22,23 and its use is routine in many clinical settings. For example, organs for transplantation are cooled rapidly after harvest, and kept cold until transplantation. Traumatically amputated limbs and fingers are also kept on ice before replantation. Complex neurological, cardiac and vascular operations are performed with the aid of hypothermic protection24–27. Hypothermia is also a very effective strategy for treating cardiac arrest28,29. Although no clinical studies have been conducted to test the therapeutic benefits of hypothermia in injured patients, numerous well designed preclinical studies clearly support this concept30. It should be emphasized that induced hypothermia and hypothermia secondary to shock are very different entities (Table 1). Induced hypothermia is therapeutic in nature, whereas hypothermia in severely traumatized patients is a sign of tissue ischaemia and failure of homeostatic mechanisms to maintain normal body temperature (Fig. 1). It is clear from the literature that rapid induction of deep/profound hypothermia (less than 15 °C) can improve the otherwise dismal outcome after exsanguinating cardiac arrest31–33. Depending on degree of hypothermia, good outcomes have been achieved with cardiac arrests of 15, 20, 30 and even 90 min in canine models34,35. Furthermore, hypothermia can be extended safely to 180 min if blood is replaced with organ preservation fluids and low-flow cardiopulmonary bypass (CPB) is continued during this interval36. It has also been demonstrated that profound hypothermia can be induced through an emergency thoracotomy approach for total body protection, with excellent long-term survival and no neurological damage or significant organ dysfunction37. Fig. 1 Open in new tabDownload slide a Aerobic metabolism in the cell guarantees adequate adenosine 5′-triphosphate (ATP) for normal physiological function and heat production (thermoregulation). b Molecular changes occurring in haemorrhage-associated hypothermia. Haemorrhage reduces the availability of oxygen and substrates, and stimulates a switch to anaerobic metabolism, leading to decreased ATP synthesis and subsequent heat production. This cellular hypoxia also stabilizes hypoxia-induced factor (HIF) 1, which activates several inflammatory and apoptotic pathways leading to increased cell injury and death. c Molecular changes associated with induced therapeutic hypothermia. Minimal metabolic activity owing to inactivation of Na+/K+-ATPase pump conserves ATP in the cell, and abolishes the need for oxygen and substrates during the circulatory arrest. Induced hypothermia also affects several molecular pathways altering the expression of many intermediates, and leads to decreased inflammation, decreased neutrophil migration and decreased apoptosis. Production of reactive oxygen species is also blunted. ADP, adenosine 5′-diphosphate; JNK, stress-activated protein c-jun kinase; iNOS, induced nitric oxide synthase; NF-κB, nuclear factor κB; COX, cyclo-oxygenase; STAT, signal transducers and activators of transcription; HSP, heat-shock protein. Adapted from reference 30 Table 1 Physiological differences between spontaneous and therapeutic hypothermia . Haemorrhagic shock . Haemorrhagic shock complicated by spontaneous hypothermia . Emergency preservation and resuscitation in haemorrhagic shock . Cardiac Decreased cardiac output, Cardiac depression, bradycardia, Induced cardiac arrest, with possible  tachycardia, hypovolaemic shock Arrhythmias with worsening hypothermia—J waves  maintenance of low-flow tissue perfusion with CPB Respiratory Variable response Central respiratory depression No spontaneous respiratory activity; need for mechanical ventilation Metabolic Increased oxygen requirements, Energy (ATP) depletion ATP preserved with reduced metabolism  with a switch from aerobic to anaerobic metabolism Supply–demand mismatch Minimal to no oxygen/substrate requirement Coagulopathy Trauma-induced consumptive Decreased platelet count and coagulation factor activity Present but irrelevant. Cellular viability is independent of blood supply. Ongoing blood loss can be recycled through CPB  coagulopathy Dilutional coagulopathy Coagulopathy reversed on rewarming Mental status Variable, but often depressed Progressive depression in mental status and eventually coma with flat EEG Deliberately kept sedated and paralysed Immune system Initiation of inflammatory response with multiple Blunted cytokine production and neutrophil migration, with increased risk of infection Blunted cytokine production and neutrophil migration  organ damage Antibiotic cover and precaution against sepsis during induced hypothermia Shivering Not observed early in haemorrhage Shivering to produce heat increases energy demand and overutilizes ATP Neuromuscular blockade or deep sedation to control shivering Hyperglycaemia Variable response Decreased insulin production and increased tissue resistance leading to hyperglycaemia Controlled and reversible . Haemorrhagic shock . Haemorrhagic shock complicated by spontaneous hypothermia . Emergency preservation and resuscitation in haemorrhagic shock . Cardiac Decreased cardiac output, Cardiac depression, bradycardia, Induced cardiac arrest, with possible  tachycardia, hypovolaemic shock Arrhythmias with worsening hypothermia—J waves  maintenance of low-flow tissue perfusion with CPB Respiratory Variable response Central respiratory depression No spontaneous respiratory activity; need for mechanical ventilation Metabolic Increased oxygen requirements, Energy (ATP) depletion ATP preserved with reduced metabolism  with a switch from aerobic to anaerobic metabolism Supply–demand mismatch Minimal to no oxygen/substrate requirement Coagulopathy Trauma-induced consumptive Decreased platelet count and coagulation factor activity Present but irrelevant. Cellular viability is independent of blood supply. Ongoing blood loss can be recycled through CPB  coagulopathy Dilutional coagulopathy Coagulopathy reversed on rewarming Mental status Variable, but often depressed Progressive depression in mental status and eventually coma with flat EEG Deliberately kept sedated and paralysed Immune system Initiation of inflammatory response with multiple Blunted cytokine production and neutrophil migration, with increased risk of infection Blunted cytokine production and neutrophil migration  organ damage Antibiotic cover and precaution against sepsis during induced hypothermia Shivering Not observed early in haemorrhage Shivering to produce heat increases energy demand and overutilizes ATP Neuromuscular blockade or deep sedation to control shivering Hyperglycaemia Variable response Decreased insulin production and increased tissue resistance leading to hyperglycaemia Controlled and reversible Adapted from reference 30. CPB, cardiopulmonary bypass; ATP, adenosine 5′-triphosphate; EEG, electroencephalogram. Open in new tab Table 1 Physiological differences between spontaneous and therapeutic hypothermia . Haemorrhagic shock . Haemorrhagic shock complicated by spontaneous hypothermia . Emergency preservation and resuscitation in haemorrhagic shock . Cardiac Decreased cardiac output, Cardiac depression, bradycardia, Induced cardiac arrest, with possible  tachycardia, hypovolaemic shock Arrhythmias with worsening hypothermia—J waves  maintenance of low-flow tissue perfusion with CPB Respiratory Variable response Central respiratory depression No spontaneous respiratory activity; need for mechanical ventilation Metabolic Increased oxygen requirements, Energy (ATP) depletion ATP preserved with reduced metabolism  with a switch from aerobic to anaerobic metabolism Supply–demand mismatch Minimal to no oxygen/substrate requirement Coagulopathy Trauma-induced consumptive Decreased platelet count and coagulation factor activity Present but irrelevant. Cellular viability is independent of blood supply. Ongoing blood loss can be recycled through CPB  coagulopathy Dilutional coagulopathy Coagulopathy reversed on rewarming Mental status Variable, but often depressed Progressive depression in mental status and eventually coma with flat EEG Deliberately kept sedated and paralysed Immune system Initiation of inflammatory response with multiple Blunted cytokine production and neutrophil migration, with increased risk of infection Blunted cytokine production and neutrophil migration  organ damage Antibiotic cover and precaution against sepsis during induced hypothermia Shivering Not observed early in haemorrhage Shivering to produce heat increases energy demand and overutilizes ATP Neuromuscular blockade or deep sedation to control shivering Hyperglycaemia Variable response Decreased insulin production and increased tissue resistance leading to hyperglycaemia Controlled and reversible . Haemorrhagic shock . Haemorrhagic shock complicated by spontaneous hypothermia . Emergency preservation and resuscitation in haemorrhagic shock . Cardiac Decreased cardiac output, Cardiac depression, bradycardia, Induced cardiac arrest, with possible  tachycardia, hypovolaemic shock Arrhythmias with worsening hypothermia—J waves  maintenance of low-flow tissue perfusion with CPB Respiratory Variable response Central respiratory depression No spontaneous respiratory activity; need for mechanical ventilation Metabolic Increased oxygen requirements, Energy (ATP) depletion ATP preserved with reduced metabolism  with a switch from aerobic to anaerobic metabolism Supply–demand mismatch Minimal to no oxygen/substrate requirement Coagulopathy Trauma-induced consumptive Decreased platelet count and coagulation factor activity Present but irrelevant. Cellular viability is independent of blood supply. Ongoing blood loss can be recycled through CPB  coagulopathy Dilutional coagulopathy Coagulopathy reversed on rewarming Mental status Variable, but often depressed Progressive depression in mental status and eventually coma with flat EEG Deliberately kept sedated and paralysed Immune system Initiation of inflammatory response with multiple Blunted cytokine production and neutrophil migration, with increased risk of infection Blunted cytokine production and neutrophil migration  organ damage Antibiotic cover and precaution against sepsis during induced hypothermia Shivering Not observed early in haemorrhage Shivering to produce heat increases energy demand and overutilizes ATP Neuromuscular blockade or deep sedation to control shivering Hyperglycaemia Variable response Decreased insulin production and increased tissue resistance leading to hyperglycaemia Controlled and reversible Adapted from reference 30. CPB, cardiopulmonary bypass; ATP, adenosine 5′-triphosphate; EEG, electroencephalogram. Open in new tab Using clinically realistic large animal models of lethal vascular injury and soft tissue trauma, it has been established that lethal vascular injuries can be repaired under profound hypothermic protection with a long-term survival rate of more than 75 per cent38. Hypothermia was found to be effective even after 60 min of normothermic shock (simulating transport time). More importantly, all of the surviving animals were neurologically intact and had normal cognitive functions. Subsequent studies have determined that, to achieve the best results, profound hypothermia must be induced rapidly (2 °C/min) and reversed at a slower rate (0·5 °C/min)39,40. Induction of hypothermia has been shown to preserve various cell types in the CNS, while providing some immunological advantages and modulating cell survival pathways41–43. The optimal depth of hypothermia is 10 °C, and decreasing the temperature to ultraprofound levels (5 °C) worsens outcomes44. The safe duration of profound hypothermic preservation appears to be about 60 min in models of polytrauma45, and it does not cause an increase in bleeding or septic complications after surgery46. Hypothermia can be induced easily using small, battery-operated, portable equipment that is suitable for austere settings47. In the event that, after induction of hypothermia, a patient is eventually found to have a non-survivable injury, hypothermia would at least preserve the organs for potential transplantation48. Hypothermia not only modulates metabolism but also influences a wide variety of cellular and subcellular mechanisms, which can be beneficial long after the period of hypothermia, such as alteration in transcription of numerous genes49. There are also some data from small animal models to suggest that similar metabolic arrest (and tissue preservation) can be achieved with other methods, such as inhalation of hydrogen sulphide50. A number of pharmacological agents have been discovered that can protect cells through direct activation of intrinsic prosurvival pathways51. However, none of these other approaches is as effective as hypothermia. Thus, an extensive body of experimental literature suggests that key organs can be preserved during repair of otherwise fatal injuries52, and a prospective multi-institutional clinical trial is scheduled to start soon that will test the feasibility of inducing profound hypothermia as a life-saving procedure in patients with fatal, but potentially fixable, injuries53. Barriers to translation Despite all the preclinical data, translation of hypothermia into trauma practice remains challenging. There are numerous reasons why this modality has not been embraced by the trauma community. First, trauma surgeons find it difficult to differentiate between spontaneous and induced hypothermia30. Induced hypothermia and hypothermia that develops as a consequence of shock are very different physiological states with markedly different outcomes54,55. Hypothermia that develops spontaneously after major trauma is a marker of injury severity, is associated with greater transfusion and fluid requirements, and predicts worse outcomes56,57. Many severely injured patients are already hypothermic by the time they reach hospital, where hypothermia gets worse owing to manoeuvres such as removal of clothing, administration of cold fluids, opening of body cavities and use of anaesthetic agents58. Maintaining normal body temperature is an energy-dependent process, and development of hypothermia suggests depletion of energy stores, and a grim prognosis59,60. Indeed, spontaneous hypothermia along with coagulopathy and acidosis are widely recognized as the lethal triad, that correlates with poor outcome after trauma13,61. Even mild hypothermia (body temperature below 35 °C) on admission was shown to correlate with increased mortality in two retrospective studies that controlled for injury severity54,60. At a cellular level, adenosine 5′-triphosphate (ATP) depletion plays a major role in the development of spontaneous hypothermia. As heat is generated through hydrolysis of ATP62, anaerobic metabolism (low ATP stores) eventually leads to the development of hypothermia. Comparison of injured patients with those undergoing elective surgery (including hypothermia for coronary artery bypass) has confirmed that ATP levels are depleted in the injured patients63. Changes in ATP levels also correlate inversely with serum lactate levels, further suggesting that hypothermia after trauma is a marker of energy depletion during anaerobic metabolism. Thermoregulatory mechanisms respond to hypothermia through a strong sympathetic surge (vigorous shivering) in an attempt to normalize the body temperature64,65, which further worsens the mismatch between energy supply and demand. Therapeutic hypothermia, on the other hand, is induced deliberately to protect vulnerable tissues from ischaemia–reperfusion injury. Lower temperature decreases tissue metabolism and oxygen demands (every 10 °C alteration in temperature results in roughly a 50 per cent reduction in global and a 63 per cent reduction in cerebral metabolism)66,67, which can be helpful during periods of poor oxygen delivery (shock). As described in other reviews, hypothermia influences numerous biological process in the body30,68. For example, lower temperature reduces inflammation, decreases free radical production, attenuates oxidative damage, reduces vascular permeability, creates an antiapoptotic environment, augments heat-shock protein, and alters extracellular matrix metabolism69–75. Theoretically, all of these changes can protect during ischaemia (haemorrhagic shock) and reperfusion (resuscitation) phases of shock. Therapeutic hypothermia is induced deliberately and does not reflect energy depletion. Furthermore, shivering can be prevented and patients carefully monitored for other undesirable side-effects. Logistical challenges Compared with other patient populations, injured patients present unique logistical challenges. Unlike elective surgery where hypothermia is induced in a controlled fashion before the onset of ischaemia (protection), hypothermia can be induced in an injured patient only after the insult has already taken place (preservation). When mild hypothermia is used to treat cardiac arrest, it is typically induced after the circulation has been restored. Furthermore, these patients have normal intravascular volumes and not uncontrolled bleeding. Injured patients, on the other hand, are hypovolaemic and bleeding actively. Hypothermia, therefore, has to be induced in the setting of a haemodynamic collapse and severe ongoing blood loss, and maintained during damage control procedures and resuscitation. This poses numerous challenges including selection of the optimal approach, training of personnel, and issues related to equipment and tools. The only way profound hypothermia can be induced rapidly is through an intravascular approach using large volumes of cold fluids (or a closed-loop system with a heat exchanger and roller pump). This can be done by placing femoral catheters, which is difficult in a pulseless patient. As most of these patients are expected to undergo emergency thoracotomy, it makes sense to place the catheter in the thoracic aorta. Furthermore, if thoracotomy reveals a controllable source of bleeding then prompt repair of injury and resuscitation (without hypothermia) is the preferred approach. A surgeon can choose to induce hypothermia if: the injuries are repairable but require additional time that could result in cerebral or cardiac damage; the injuries require surgical exposure that would be facilitated by initiating CPB with complete control of flow; or the extent of the injuries is unclear and the surgeon requires more time for complete exploration, while maintaining viability of critical organs. This is especially true in the setting of multiple injuries that require exploration of different body cavities. In the forthcoming multi-institutional feasibility trial of EPR53, hypothermia will be induced through an open-chest approach using commonly available fluids (ice-cold saline) and routine CPB equipment. As appropriate patients are unlikely to arrive in the trauma centre during regular working hours, a fully trained team must be available around-the-clock. Realistically, this cannot be the cardiac surgery team, and the on-call trauma team will have to assume responsibility for implementation of the protocol. The trauma surgeon will insert a catheter directly in the descending thoracic aorta rapidly to induce hypothermia to a target temperature of 10–15 °C. This is best done using a roller pump and a closed-loop system with heat exchanger, but can also be achieved simply by infusing large volumes of ice-cold saline. Then, the patient will be transferred rapidly to the operating room for damage control surgery, and the cardiac surgery team will set up conventional CPB. Using a two-team approach, the trauma team will focus on haemorrhage control whereas the cardiac surgery team will resuscitate and rewarm the patient on CPB. Potential side-effects of hypothermia Temperature influences numerous systems in the body, and induction of hypothermia, while offering cellular protection, has potential side-effects (Table 2). These include cardiac arrhythmias, coagulopathy, infection and altered drug metabolism30,68. Table 2 Potential complications of induced hypothermia Changes in drug metabolism Coagulopathy Dysrrhythmias Electrolyte shifts/disturbances Ileus Increased creatinine Increased liver enzymes Insulin resistance Pancreatitis Pneumonia Postcooling diuresis Wound infections Changes in drug metabolism Coagulopathy Dysrrhythmias Electrolyte shifts/disturbances Ileus Increased creatinine Increased liver enzymes Insulin resistance Pancreatitis Pneumonia Postcooling diuresis Wound infections Incidence of complications and their importance varies with the clinical scenario, depth and duration of hypothermia. Open in new tab Table 2 Potential complications of induced hypothermia Changes in drug metabolism Coagulopathy Dysrrhythmias Electrolyte shifts/disturbances Ileus Increased creatinine Increased liver enzymes Insulin resistance Pancreatitis Pneumonia Postcooling diuresis Wound infections Changes in drug metabolism Coagulopathy Dysrrhythmias Electrolyte shifts/disturbances Ileus Increased creatinine Increased liver enzymes Insulin resistance Pancreatitis Pneumonia Postcooling diuresis Wound infections Incidence of complications and their importance varies with the clinical scenario, depth and duration of hypothermia. Open in new tab Induction of hypothermia causes an initial increase in heart rate, cardiac output and systemic vascular resistance, followed by a decrease in heart rate and cardiac output once temperatures are less than 30 °C. Heart rate slows down markedly below 28 °C, which can eventually lead to asystole by the time deep hypothermia is achieved. As induced hypothermia also reduces metabolic demand, this negative chronotropic effect should not significantly disrupt the balance of energy supply and demand. Moderate hypothermia has also been associated with increased risk of cardiac arrhythmias: J waves, first-degree heart block, and prolonged QT interval76. During a trial of moderate hypothermia in children with traumatic brain injury, increased rates of arrhythmia were observed that were manageable with standard interventions; a trial of moderate hypothermia for neonatal encephalopathy similarly reported more frequent episodes of bradycardia77,78. It is uncertain whether these findings can be generalized to adults, but continuous monitoring of cardiac and metabolic parameters is essential during hypothermia. The potential for complications is minimal for mild to moderate hypothermia, but induction of deep to profound hypothermia typically requires mechanical haemodynamic support. There are no good data to support the common belief that hypothermia causes coagulopathy. Most probably it occurs in association with shock: disrupted haemostatic mechanisms, acidosis and tissue injury cause both. Direct effects of hypothermia on coagulation are poorly understood, and historical data are limited by the design of the studies. Most of the coagulation reactions have been studied at room temperature; minimal data exist on reactions at 37 °C (normal body temperature), and almost no data on very low temperatures (less than 20 °C). Data generated from long-term cold exposure/storage of blood products/components do not apply well to short durations of hypothermia in vivo. Thus, it is not surprising that the incidence of coagulopathy is inconsistent in preclinical and human studies of hypothermia. Although suffering from the limitations mentioned above, there are studies suggesting that hypothermia causes a decrease in platelet count and function79–82, which is typically reversed with rewarming83. In addition, temperature-specific enzymatic reactions in the clotting cascade can be affected, especially below 34 °C76,80,82,84. However, the actual rate of coagulopathy with hypothermia remains variable. In the preclinical setting, mild hypothermia has been shown to increase prothrombin time (PT) and partial thromboplastin time (PTT) in some studies85, but not in others86–88. In humans, hypothermia during surgery has been associated with increased blood loss and need for transfusion89. A trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy reported higher PT, lower platelet count, and more requirements for platelet and plasma transfusion in the hypothermia group90, but these were not confirmed in other large studies91. In injured patients, platelet function was found to be impaired, but not fibrinolysis92. In patients with traumatic brain injury, hypothermia was associated with longer PT/PTT and lower platelet counts in one study93, but not in three others78,83,94. A meta-analysis of clinical trials on traumatic brain injury showed that PTT tended to increase slightly with hypothermia95. Even when laboratory parameters of coagulation are affected, their clinical significance remains unclear96,97. Until better data become available, it should be assumed that hypothermia (especially deep and profound) carries a risk of coagulopathy, and that patients should be monitored closely. Interpretation of laboratory values must be done with caution as samples are typically warmed to 37 °C, potentially masking the effects of hypothermia. In vitro data have shown that coagulopathy during hypothermia is easily corrected with rewarming97. Most importantly, the potential risks of coagulopathy must be balanced against the potential advantages of hypothermia in any given setting. A brief interval of reversible coagulopathy may be an acceptable risk if hypothermia makes it possible to perform a life-saving procedure. Hypothermia blunts the immune response, and decreases cytokine production and neutrophil migration. Although this immunological attenuation protects tissues from reperfusion injury and inflammatory damage, it may also increase the risk of infection. In a randomized clinical trial, maintenance of normal body temperature during elective surgery reduced wound infections compared with perioperative mild hypothermia98. Studies have also reported increased pneumonia in patients receiving therapeutic hypothermia for traumatic brain injury99,100, although these patients are clearly at high risk of developing pneumonia as a result of prolonged mechanical ventilation, with or without hypothermia. Others have shown no increase in infection rates with the use of hypothermia101. As with coagulopathy, risks of infection must be balanced against the life-saving potential of this intervention. The duration and depth of hypothermia are critical variables that influence infection rates; a short duration of profound hypothermia is not the same as prolonged mild to moderate hypothermia. For example, no infectious complications were noted during 6 weeks of observation in an animal model in which lethal vascular injuries were repaired along with colonic injuries during 60 min of profound (10 °C) hypothermia46. However, it is reasonable to administer a short course of prophylactic antibiotics before instrumentation and induction of hypothermia. Similarly, all standard preventive measures and surveillance strategies for nosocomial infections should be implemented in patients who are hypothermic. Hypothermia decreases the systemic clearance of drugs metabolized by cytochrome P450 by between approximately 7 and 22 per cent per °C below 37 °C. The therapeutic index of drugs is narrowed during hypothermia and the pharmacokinetics of many drugs may be altered102. For drugs with a long half-life, rewarming may be a time of increased drug concentration with an intact receptor response (potential for toxicity). Physicians should be aware of these changes and adjust pharmacotherapy accordingly. However, this is an area where good studies are lacking and there is a clear need for more research. Enrolment in clinical trials: consent and cost issues Clearly, injured patients who are most likely to benefit from induction of profound hypothermia are unable to give consent. It is also highly unlikely that surrogates/family members could be contacted within the short window of opportunity. Thus, the only realistic method for making these potentially life-saving strategies available to the appropriate patients would be through a waiver of informed consent103. To protect the rights and welfare of the subjects, investigators must fulfil many requirements, including community consultation and rigorous reviews by many regulatory bodies. This slow and laborious process requires dedicated personnel and a very generous funding source. As hypothermia has no intellectual property potential and is unlikely to attract funding from the pharmaceutical industry, the only viable option is to support this critical research from public funds. Hypothermia is clearly a double-edged sword; unless managed carefully, its induction can be associated with a number of complications. Appropriate patient selection requires a thorough understanding of the preclinical literature. Clinicians must also appreciate the enormous influence that temperature exerts on various cellular mechanisms. A workshop was recently held at the National Institutes of Health and funded by the US Department of Defense to evaluate the benefits and risks of induced hypothermia, focusing specifically on the current state of knowledge and potential applications in injured patients (HYPOSTAT workshop, February 2011; Chair: H. B. Alam). A panel of experts was brought together to provide clinical guidelines for the use of hypothermia, as well as to make recommendations for future research in this arena. There is strong enthusiasm among trauma clinicians, and support for advancing new frontiers in clinical applications as well as in new research. A number of areas have been identified that need additional research (Table 3). Table 3 Potential areas for research Studies to define better the mechanisms that are critical to the benefit of hypothermia across different insults Effect of hypothermia on coagulation, platelet function and bleeding in clinically realistic models Impact of temperature alteration on drug metabolism and drug effect Studies on the combination of hypothermia with novel pharmacological agents (cytoprotective agents) to determine whether hypothermia expands the therapeutic window for drug therapies, or whether drugs expand the window for hypothermia Making additional funding available for clinical trials of therapeutic hypothermia Studies to define better the mechanisms that are critical to the benefit of hypothermia across different insults Effect of hypothermia on coagulation, platelet function and bleeding in clinically realistic models Impact of temperature alteration on drug metabolism and drug effect Studies on the combination of hypothermia with novel pharmacological agents (cytoprotective agents) to determine whether hypothermia expands the therapeutic window for drug therapies, or whether drugs expand the window for hypothermia Making additional funding available for clinical trials of therapeutic hypothermia Open in new tab Table 3 Potential areas for research Studies to define better the mechanisms that are critical to the benefit of hypothermia across different insults Effect of hypothermia on coagulation, platelet function and bleeding in clinically realistic models Impact of temperature alteration on drug metabolism and drug effect Studies on the combination of hypothermia with novel pharmacological agents (cytoprotective agents) to determine whether hypothermia expands the therapeutic window for drug therapies, or whether drugs expand the window for hypothermia Making additional funding available for clinical trials of therapeutic hypothermia Studies to define better the mechanisms that are critical to the benefit of hypothermia across different insults Effect of hypothermia on coagulation, platelet function and bleeding in clinically realistic models Impact of temperature alteration on drug metabolism and drug effect Studies on the combination of hypothermia with novel pharmacological agents (cytoprotective agents) to determine whether hypothermia expands the therapeutic window for drug therapies, or whether drugs expand the window for hypothermia Making additional funding available for clinical trials of therapeutic hypothermia Open in new tab Acknowledgements An executive summary of the recent HYPOSTAT workshop ‘Hypothermia in Trauma: a New Crossroads’ will be available shortly on www.nih.gov. 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. TI - Translational barriers and opportunities for emergency preservation and resuscitation in severe injuries JF - British Journal of Surgery DO - 10.1002/bjs.7756 DA - 2011-12-22 UR - https://www.deepdyve.com/lp/oxford-university-press/translational-barriers-and-opportunities-for-emergency-preservation-ytu0Cc7zFu SP - 29 EP - 39 VL - 99 IS - Supplement_1 DP - DeepDyve ER -