• trauma management
• hypothermia
• hemorrhage
• cardiac arrest

Patients who suffer a cardiac arrest from trauma have almost no chance of survival. They exsanguinate and suffer irreversible vital organ damage before surgeons are able to obtain haemostasis, despite rapid transport by emergency medical services, airway control, massive transfusions and an emergency department thoracotomy.

Hypothermia has the potential to decrease cellular and vital organ need for oxygen, potentially buying time for surgical haemostasis and successful resuscitation. But exposure or spontaneous hypothermia, which frequently occurs in severely injured trauma patients, is associated with worse outcomes1 and is consequently included in the so-called triad of death (hypothermia, coagulopathy and acidosis). To manage this situation, trauma surgeons have taken a damage control approach in the operating room, only performing absolutely necessary procedures to stop bleeding and minimise contamination.2 Standard management of trauma patients includes active measures to prevent and treat hypothermia. Nonetheless, many laboratory studies have demonstrated that mild (32°C–34°C), controlled, therapeutic cooling during or after haemorrhagic shock can improve survival.3 Why the laboratory findings and clinical associations are so different remains unclear. Is it shivering? Is it the stress response to hypothermia? Both of these are suppressed by anaesthesia and sedation in the animal models. Is it differences in the coagulation systems of different species or the amount of tissue trauma? Is it the use of banked blood in humans and the use of the animal’s own, shed blood in the animal models? At this point, we don’t know.

With this dichotomy between laboratory and clinical findings in mind, it seems counterintuitive and perhaps even heretical that hypothermia could be life-saving in the most seriously ill trauma patients. Yet, in this issue of the journal, Moffatt et al, have reviewed the use of very deep levels of hypothermia (10°C–15°C) for potentially saving trauma patients who have suffered cardiac arrest from exsanguination.4 The authors have done an excellent job of synthesising a complex series of animal experiments in their review. The use of hypothermia to which they refer is now called emergency preservation and resuscitation (EPR). The original idea was conceived by Dr Peter Safar, a world-renowned resuscitation researcher, and Colonel Ron Bellamy, a leader in military medicine, who reviewed data regarding casualties from the Vietnam War. They recognised that many of these injured soldiers had potentially survivable injuries if surgical intervention could have occurred in a more timely fashion. While some died of their wounds immediately, others died over the course of 30–60 min, a time frame in which a novel therapy could be applied. They theorised that it would be possible to rapidly induce a state of ischaemic tolerance, using hypothermia and/or pharmacological approaches, to buy time for transport and a damage control approach to surgical haemostasis for the exsanguinating soldier.

Studies in both canines and swine have demonstrated that induction of EPR with rapid cooling to 10°C using intra-arterial infusion of large amounts of ice-cold fluid or a cardiopulmonary bypass (CPB) system can allow at least 1 hour, and possibly up to 2–3 hours, of circulatory arrest, during which surgical haemostasis could be achieved after clinically relevant injuries.5 In one study, this approach allowed almost all animals to survive while no animals survived after standard resuscitation.6 Rodent studies have begun to explore the biochemical mechanisms that lead to cellular damage, as well as those that underpin the beneficial effects of hypothermia, during and after EPR.7 Once these mechanisms are better understood, it may be possible to add targeted drugs or specialised fluids to the EPR process to decrease the need for such low levels of temperature. These approaches could also allow earlier initiation of EPR by less experienced personnel since the current, cold fluid strategy requires a high level of expertise for placement of very large cannulas directly into the arterial system and management of a CPB system. So far, however, laboratory studies of multiple drugs have not demonstrated benefit beyond the effects of hypothermia.8

Postcardiac arrest care has become an important clinical topic, with national guidelines suggesting benefit of targeted temperature management (33°C–36°C) for at least 24 hours following resuscitation.9 In one EPR animal study, there was a suggestion that more prolonged postresuscitation mild hypothermia was beneficial.6 Intuitively, more prolonged hypothermia may be beneficial after more severe initial insults. Ideally, we will develop specific biomarkers to provide a rational approach to titration of postarrest therapies, such as targeted temperature management.

In their review, Moffatt et al, suggest that there may be species differences in the absolute period of ischaemic tolerance with EPR.4 For example, >60 minutes of circulatory arrest in rats leads to poor outcomes, yet dogs have survived after as long as 3 hours of arrest. While it is true that there are species differences in ischaemic tolerance based on resting metabolic rates, there are also important logistic differences between rodent and large animal models. These include the ability to provide clinically relevant intensive care, including prolonged endotracheal intubation and invasive haemodynamic monitoring, and to obtain comprehensive evaluations of neurological functioning. Humans can certainly survive very lengthy intensive care unit stays and can also undergo rehabilitation, which is not typically included in animal studies.

In the animal models, the pre-existing physiological insult before induction of EPR is controlled. The worse the state of shock prior to cardiac arrest, the worse the outcome. It is possible to plot out the severity of this insult that will still allow normal functional recovery. From a clinical standpoint, however, it is impossible to know the exact severity of this insult prior to considering the initiation of EPR. This brings us to the ultimate question: Will the findings in clinically relevant, large animal studies translate into success with humans?

In their discussion, Moffatt et al refer to the EPR for Cardiac Arrest from Trauma Trial (NCT01042015) that is currently enrolling subjects at the RA Cowley Shock Trauma Centre of the University of Maryland Medical Center.10 This safety and feasibility study is enrolling victims of penetrating trauma who have suffered a cardiac arrest from presumed exsanguination within 5 min of hospital arrival. If the patient does not have restoration of spontaneous circulation following a resuscitative thoracotomy, an arterial CPB cannula will be inserted into the descending aorta to enable infusion of ice-cold saline, with drainage via opening the right atrial appendage. The goal will be to decrease tympanic membrane or nasopharyngeal temperature to 10°C as rapidly as possible. Once the goal temperature is reached, the patient will undergo a damage control operation, followed by reperfusion and rewarming using CPB. The primary outcome will be survival to hospital discharge with minimal neurological deficits. Ten subjects who undergo the procedure will be compared with 10 control subjects who undergo standard care because the complete EPR team is not available.

If the feasibility of EPR can be demonstrated, how can this highly invasive, highly technical intervention become more broadly applied? There has been some work on low-cost, compact CPB systems.11 Novel designs for cannulas and improved, preprimed CPB circuits would also help. In the future, development of pharmacological approaches with combinations of drugs and fluids could drastically simplify the process of EPR induction and allow many more providers to initiate EPR. The ultimate goal of using EPR as part of the damage control approach to resuscitation will be to save many of the lives that we currently cannot, as we lose the race against the clock to save them.