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Bloody Battle

Image © Commonwealth of Australia Department of Defence

Image © Commonwealth of Australia Department of Defence

By Geoffrey P. Dobson

Soldiers suffering catastrophic blood loss often die on the battlefield before they can be evacuated, but emerging science is targeting new ways to stabilise the heart and circulation to buy time and save lives.

Imagine that you are leading a special unit in pursuit of enemy insurgents along a mountainous track in low light conditions. You step onto a pressure plate buried just beneath the surface.

The explosion is massive. You hit the ground hard with both legs blown off. Your life has changed in a footstep.

After the dust and smoke clears, your mate arrives to assist. He sees your body rapidly bleeding out and going into shock, and notices the heel of your boot imbedded into a gaping hole in your abdomen. What can he do?

The new enemy is time. The “Golden Hour” no longer exists – your mate has only seconds to control the bleeding with tourniquets and pro-clotting bandages in what is called the Platinum 5 or 10 minutes. Your team radios for help but the hostile terrain and bad weather hampers early evacuation, so there may be a delay of many hours.

In the civilian world, we cannot imagine bodily carnage of this magnitude. Nor can we imagine the difficulties of working to save a life in a hostile environment deep in enemy territory under low light conditions, extreme temperatures, major resource limitations and prolonged evacuation times. These complicating factors, along with command and tactical decisions affecting healthcare and evacuation times, pose a different set of constraints than in the civilian pre-hospital emergency setting.

Haemorrhage is responsible for up to 50% of trauma deaths on the battlefield and 30–40% of deaths in the civilian population, with one-third to one-half occurring in the prehospital period. On the battlefield up to 25% of bleeding casualties may be potentially salvageable.

Currently there is no small-volume fluid to promptly stabilise a soldier at the scene before profound shock sets in. The major problem with existing resuscitation fluids is that many negatively impact on the survival outcome by further promoting bleeding, acidosis and hypothermia. Fluids containing dextrans and starches have received a lot of attention in the past 15 years, but in 2010 key opinion leaders from military and trauma centres concluded that they may not be optimal for battlefield or civilian use:

While the widespread training of medics in tactical combat casualty care has clearly saved lives, the use of saline and colloid starch by medics on the battlefield does not represent a significant technological advance in ability since saline was first used for resuscitation in 1831.
Col. Blackbourne, Butler, Pruitt et al. J .Trauma 69(Suppl.1), S1–S4.

Guidelines for Battlefield Medicine
Tactical Combat Casualty Care (TCCC) was the brainchild of the US Naval Special Warfare Command. In 1996, the first TCCC guidelines for use by Special Forces, medics and parachuting rescue personnel were published in the journal Military Medicine. The guidelines are continually updated by a multi-service specialist committee, and a TCCC course is incorporated in most advanced western armies with extraordinary success. The course instructors are combat veterans with extensive knowledge and experience in the areas of combat medicine and tactical field care.

The number one rule of TCCC is that the best medicine is tactical fire superiority. Care can only begin when it is safe to do so.

Surviving trauma and massive blood loss depends on prompt strategic placement of tourniquets and bandages followed by traditional airway, breathing and circulation methods and secondary survey and stabilisation methods. If the casualty has no measureable pulse or is dehydrated, fluid is administered intravenously to raise blood pressure into a “permissive range” that is sufficient to nourish vital organs and keep the soldier alive but not high enough to disrupt clotting and hence cause further bleeding and rapid death. After bleeding is controlled, the casualty can be evacuated when it is practical.

It is this early window of tactical combat casualty care that requires new pharmacological innovation to buy more time and save lives. There is no small-volume resuscitation fluid that optimally rescues, stabilises and protects the critically wounded.

Rescuing and Stabilising the Heart and Circulation of the Critically Wounded
In the same year that the TCCC guidelines were introduced in the US, a global challenge was launched by an independent panel of resuscitation science investigators which wrote:

We urgently require drug therapy to RESCUE and STABILISE the heart ... before shock and multiple organ failure occurs from massive inflammatory response. Unfortunately, in contrast to the extraordinary military success of TCCC, there is still no evidence-based, first responder drug therapy that rescues and stabilises the heart, reduces inflammation, restores clotting status and improves survival following massive blood loss.

In 2008 we set out to develop a small-volume high-salt solution with adenocaine® and magnesium for haemorrhagic shock resuscitation. Over the past few decades, small-volume high-salt solutions have received a lot of attention because of their ability to draw water from tissue spaces into the blood space and thereby increase blood volume, pressure and cardiac output. The problem is that its effect is short-lived and the blood pressure falls again to life-threatening shock levels.

To counter this, different colloids such as starches and dextrans have been added to keep blood pressure higher for longer periods during resuscitation. One of these fluids, RescueFlow©, has been approved in 17 European countries for this purpose but not in the US. RescueFlow© is also not widely used on the battlefield because of conflicting results.

The most common intravenous fluid used for battlefield resuscitation is Hextend©, which is a blood volume expander. However, larger volumes of Hextend© are required to raise blood pressure effectively. A major problem with using large volumes of fluid after trauma and massive blood loss is the dilution of clotting factors which, on top of an already “thinning” of the blood from the shock process itself, can promote further bleeding and worsen the condition.

The first study we undertook was to examine the effects of Dextran-70 and starches on cardiac function and stability following 40% blood loss in rats. In 2010 we reported in the Journal of Trauma that both colloids in small-volume high-salt solutions had a number of untoward effects and the starches increased mortality. The data supported the idea that colloids may not provide optimal protection.

In a second study using the same rat model of 40% blood loss, we showed that a small volume (eight drops) intravenous solution of high salt with adenocaine® and magnesium (without colloids) slowly and predictably raised the blood pressure into a lower permissive range. This result was in direct contrast to a high-salt solution alone.

More recently we have tested our small-volume adenocaine® fluid in a battlefield rat model of 60% blood loss and found a gentle increase in blood pressure into the “permissive” range, stable haemodynamics, and an unexpected 100% rate of survival. In direct contrast, only one rat receiving RescueFlow© survived.

Our 100% survival rate is significant. In the civilian setting a blood loss of 60% with a systolic pressure less than 50 mmHg carries a risk of death of 95% in 18 minutes. To our knowledge, no small volume fluid therapy has achieved 100% survival after 60% blood loss.

It is tempting to speculate that our small-volume resuscitation fluid – with its gentle pressure-raising ability and anti-inflammatory and coagulation corrective properties – could offer a new “survival triad” paradigm for major trauma and massive blood loss. There is also some clinical evidence that the drugs in our new fluid therapy may reduce pain from the injury and from local inflammation, which may be significant for war-related or civilian traumatic injuries.

Further research is required to establish if we have raised the bar and met the 1996 global resuscitation challenge and whether our innovation represents “a significant technological advance in ability since saline was first used for resuscitation in 1831”. Only time will tell. However, as scientists we do have an ethical and moral obligation to our soldiers and fellow citizens to find out sooner rather than later.

Box: Buying Biological Time
Time is the critical factor for the management of all forms of major trauma. In the tactical environment there are three “windows” of opportunity for treating the soldier following major trauma and blood loss.

1. Care Under Fire refers to care rendered at the scene of the injury, which is limited to treatments carried by each combatant and/or the medic. This tiny window of life-saving opportunity is often called the Platinum 5 or 10 minutes.

2. Tactical Field Care is the care rendered once the casualty and/or the unit is no longer under hostile fire. Medical treatment is still limited and the window of care encompasses the Golden Hour.

3. Combat Casualty Evacuation Care is the care provided while the casualty is being evacuated to a higher echelon of care using aircraft, ground vehicle or boat, and may take a number of hours.

Box: Suspended Animation
Our new small-volume resuscitation fluid was developed from a concept we have introduced into cardiac surgery. In 1998 we asked whether the human heart could be pharmacologically manipulated to operate more like the heart of a natural hibernator. Hibernating animals do not flood their cells with high-potassium salts as they turn their metabolism down by 98% to survive the harsh winter months. Similarly surgeons stop the hearts of patients undergoing cardiac surgery.

Adenocaine® at high concentrations places the heart in a state of suspended animation during cardiac surgery, while at lower concentrations it resuscitates the heart after surgery. Our revolutionary low-potassium adenocaine® and magnesium solution is currently used in the USA, and is soon to be introduced into Europe. It is the lower concentrations, combined with a small-volume high-salt solution, that we use in tactical combat casualty care for severe to massive blood loss.

Geoffrey P. Dobson is Personal Chair of the Heart Research Laboratory at James Cook University. He is the founding director of Hibernation Therapeutics Global Pty Ltd (www.adenocaine.com) and is the sole inventor on nine patents (issued and pending) relating to adenocaine. The research described here was recognised at the American Heart Association’s Resuscitation Science Symposium last year when he and MSc student Hayley Letson were awarded the best-of-the-best abstracts (trauma), and this year he was invited to present the resuscitation research at NATO’s Operations Medical Conference.