I remember sitting at the Mid-Atlantic Anesthesia Research Conference in the mid-2010s and being absolutely stunned when Dr. Ronald Miller walked through the door to give a keynote speech. This was not a large conference, and to have the literal grandfather of modern anesthesia speak seemed discordant. As he spoke, he revealed that he had served in the US Navy during Vietnam in 1968 before returning to his prolific academic career, and his presence at this conference hosted at a Navy hospital began to make more sense.

I do not remember many specifics from that lecture, but I will never forget his line, “Fresh warm whole blood is the Nectar of the Gods.” He went on to describe the borderline-miraculous qualities of this product, which at that time was regularly collected from pre-screened servicemember donors on-site in a process known as a walking blood bank. Anyone familiar with resuscitative medicine understands the need to balance the yellow stuff (plasma and platelets, the stuff that makes you clot and stop bleeding to death) with the red stuff (red blood cells, the stuff that carries oxygen from your lungs to your brain, heart, kidneys, muscles, etc). 

In short, if you only resuscitate a hemorrhaging patient with yellow stuff (plasma and platelets), you will lose the ability to carry oxygen and your brain and heart will be damaged because they are choking to death because you have lost all of their red blood cells. Likewise, if you solely resuscitate with red stuff (red blood cells), the patient will just continue to bleed to death because they have lost their ability to make the platelet plugs that we know as clots. In the worst case, you resuscitate with normal fluids that you might give a dehydrated patient, and then you just keep bleeding and the blood that you have left is so anemic that it cannot effectively carry oxygen.

‘Fresh warm whole blood is the Nectar of the Gods’

Dr. Ronald Miller

Traditionally, a massively hemorrhaging patient will receive a balanced resuscitation where one unit of red stuff (red blood cells) is given along with one unit of each of yellow stuff (plasma and platelets respectively). This is thought to approximate whole blood, and in the United States, this 1:1:1 ratio is the standard of care for trauma resuscitation. 

Enter Whole Blood. This is a very straightforward blood product. It is blood that has been collected and stored, and when needed, it is warmed and administered to a patient. It contains both yellow and red stuff (plasma, platelets, and red blood cells) because it is just blood, plain and simple. Having managed many massive resuscitations, the simplicity of hanging a unit of whole blood as opposed to keeping track of a balanced resuscitation amid the chaos of a polytrauma cannot be overstated. Warm Whole Blood, as Dr. Miller described, is Whole Blood that has never been cooled for storage, and its efficacy at restoring blood volume, helping stop bleeding, and replenishing oxygen delivery to vital organs is theoretically the highest of any resuscitative fluid available, thus earning the moniker “Nectar of the Gods” from Dr. Miller. 

So there it is, fresh Warm Whole Blood is the ideal resuscitative fluid. It works the best so we should use it for everyone.

Well, not quite. 

There are multiple reasons the FDA moved away from Whole Blood transfusions in favor of separating donor blood into its components of red and yellow stuff, a practice known as “Component Therapy”. The primary reason for this has to do with blood type. Suffice it to say that Red and Yellow stuff are generally opposites, and as always, opposites tend to be compatible. If you give someone the wrong blood type, there is a significant risk that either antibodies in the recipient’s blood or antibodies in the donor blood product will attack and destroy the red blood cells in the recipient. This attack causes the red blood cells to burst, resulting in critically high levels of certain electrolytes and proteins that can, in severe cases, stop the heart. This phenomenon is potentially catastrophic to most resuscitative efforts and great measures are taken to avoid these ‘acute hemolytic transfusion reactions’.

The universal donor red blood cell type is O while the universal donor yellow stuff (plasma) blood type is AB. Red blood cells with an O blood type are not destroyed by the most powerful antibodies in the recipient’s body if present, while AB plasma does not contain any of the most powerful antibodies that might destroy the recipient’s red blood cells. This is why we will give Type O red stuff and Type AB yellow stuff to patients who need emergency resuscitation. We do not have time to test their blood for compatibility, and we are trying to minimize the antibody-mediated immune response and avoid the catastrophic ‘red-cell-bursting’ scenario previously described. 

The issue we have is that when we give O Whole Blood, we are giving O red blood cells (universal donor) and O plasma. O plasma is the opposite of a universal donor and may contain those powerful, red blood cell-destroying antibodies. We overcome this risk by testing for the relevant antibodies in O Whole Blood, quantifying their presence using a lab test called a titer. A low titer indicates a weak antibody response, and we deem this safe to administer to patients in emergencies. 

This immunogenic (antibody-mediated) response is a major reason why the US FDA has not approved Whole Blood for general use, reserving it instead for traumatic hemorrhage. That said, the practice of identifying ‘Low Titer O-Whole Blood’ (LTOWB) for transfusion has greatly improved safety and LTOWB has been used for decades in battlefield medicine. 

Unfortunately, the logistics of maintaining a supply of LTOWB is challenging, given its maximum 35-day lifespan and the need to maintain a 1-6 degree Celcius storage temperature. This is a long period of cold chain storage when sending blood from the Continental United States to far-distant battlefields. Walking blood banks can help solve some of these problems by drawing blood from servicemembers as needed, but this has the potential to degrade the donor’s combat effectiveness and is likely of limited utility in active combat operations. 

In Large Scale Combat Operations (LSCO) as we may face in a future conflict, the quantity of expected casualties demands that contingency courses of action beyond using the stored whole blood with its limited shelf life or a walking blood bank be considered.

Above is an image from a past presentation I have given on the role of hemoglobin-based oxygen carriers (HBOCs, more commonly known as synthetic blood). As we consider the realities of scale and distance future conflict, it becomes clear that LTOWB is clinically the ideal resuscitative fluid, but it falls short of the logistical necessities. Other options such as the combination of shelf-stable and antibody-free HBOCs (synthetic red stuff) and freeze-dried plasma (long-lasting yellow stuff) could emerge as an option for a reasonable Whole Blood Analogue during contingency operations (more to come in a future blog post). It may not be Dr. Miller’s Ambrosia, but it may be good enough to keep service members alive long enough to undergo damage control surgery.

When considering the brutal pragmatism that accompanies LSCO, the time is now to meaningfully explore all potential options for austere resuscitative medicine. This should be done in addition to building out the supply chains that ensure an uninterrupted supply of LTOWB to the front lines of tomorrow. Only by maximizing the options available for the corpsman, medic, and provider downrange can we ensure that we will have fewer dead friends when the dust eventually settles.

For further reading on this topic, the Joint Trauma System CPG on Whole Blood Transfusion which describes most of this in slightly more technical terms is posted below: