Replace What’s Lost with What’s Lost? 

Considering Prehospital Whole Blood for Life-Threatening Bleeding.

“Permissive hypotension in trauma” is a term with which we are now all well-acquainted. Severely injured victims of trauma suffering shock from incompressible hemorrhage do not benefit by being inflicted with the old school intravascular crystalloid flood, converting their remaining blood to dilute Kool-Aid, inducing acidemia, hypothermia and potentially, “popping the clot” due to the restoration of blood pressure in excess of what is needed to survive to definitive care. Stand down on those two 8.5 F introducers and the saline in pressure bags in your holsters there, cowboy!  All well and good, but how permissive can we be?

As an EMS physician, how do I provide actionable field guidance for limited crystalloid resuscitation for the providers in the trenches?  Is it a number, for example 90 systolic, or is it some improvement in mentation or a palpable pulse?  It is a difficult situation to be in the back of an ambulance or helicopter caring for someone who is suffering from hemorrhagic shock and be advised against bolusing with crystalloid. The publication of a seminal paper by Bickell et al. demonstrated that patients with penetrating injuries to the torso in an urban environment suffered excess mortality if given IV fluid prehospital.[^1]  This and subsequent studies have caused us to carefully reconsider how much pressure is enough as well as to consider other therapies in the prehospital setting.

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While I was trying to revise the field protocols for this condition, I had the good fortune to be at an event where I was able to spend some time with a renowned trauma surgeon. This surgeon has published extensively on his military and civilian experience in resuscitating devastating trauma to a remarkable level of successful outcomes. He was my target of opportunity for a definitive answer on the target for limited crystalloid resuscitation in the field. I asked that question and was a bit surprised by his response: “Don’t give ANY crystalloid. It’s poison.”  Say, again?

“Simple, don’t give crystalloid, it’s all poison, it kills people.” I pressed: my people are in the field, miles from a center offering surgery, the patient’s blood pressure is barely palpable, they are ashen, incoherent after a major MVC…nothing?  Nothing?  Doesn’t seem like an answer that will really work. “Give whole blood. The patients need whole blood. We’ve shown that in battlefield medicine and in our trauma center.”

Ultimately, in the absence of whole blood he said that he would give just enough crystalloid to achieve a palpable radial pulse; still the answer he strongly endorsed was whole blood. The literature on prehospital crystalloid includes extremes of view, but a recent review allows for the cautious use of prehospital crystalloid [^2] and the most recent ATLS guidelines recommend use of up to 1 liter during initial assessment.[^3]

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The military’s experience with early aggressive use of blood products in conjunction with early achievement of hemostasis, including battlefield tourniquet use and surgery, has established new standards for what is achievable in hemorrhagic shock. Military medicine deployed specially trained field teams consisting of emergency nursing, paramedics and physicians that brought care to the patient using a large helicopter platform for advanced trauma care en route to surgical facilities. Included in their armamentarium was a “cold box” with four units of cooled banked blood to be used at the forward physician’s discretion.[^4]

O’Reilly et al. in a retrospective cohort trial of 1,153 combat casualties compared 97 severely injured patients who received prehospital transfusion to controls matched by propensity scoring who did not receive prehospital blood and showed that mortality was less than half (8.2% vs. 19.6%, p<0.001). Unfortunately, due to multiple uncontrolled variables this could not solely be attributed to transfusions.[^5] 

The military recognized the limitations of transfusion of red cells alone, which included the coagulopathy associated with the preservative (citrate) as well as the inherent lack of other blood components for coagulation. They addressed this by instituting the availability and use of fixed ratio component therapy with plasma and platelets in addition to the prbc. In an example of the past becoming the future, whole blood therapy was viewed very favorably by virtue of its ability to replace what had been lost while intrinsically decreasing the complexity of banking and administering the components. The availability of “warm donors” of blood, i.e. the use of fellow soldiers’ blood was brought forward as a practical solution as well. Use of warm fresh whole blood was studied as early as 2009 and was found to be associated with improved 30-day survival.[^6]

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The question that is now being asked by some high-volume trauma systems is whether this battlefield best practice can be successfully translated into the civilian world.

Prehospital use of blood products has been fairly standard for fixed wing interfacility transport in which there is a known or anticipated need for blood that is obtained from the blood bank prior to flight and administered en route by flight teams. Recently there has been many published examples of helicopter scene responses in which packed red blood cells (prbcs) are administered including a systematic review.[^7] Brown et al. reported retrospective data on 244 instances of prbcs from 2007 to 2012 for helicopter transport of trauma patients to a level 1 trauma center. They demonstrated improved short-term survival, but no improvement in long term survival.[^8] Use of prehospital transfusion of cold-stored whole blood in urban medicine has been carefully examined and felt to be reasonable [^9], the expense and logistics has checked rapid adoption in addition to the hesitance to adopt what some deem a controversial therapy.

The Southwest Texas Regional Advisory Council (STRAC) Air Medical Provider Advisory Group, or AMPAG, initiated an ambitious program in January 2018 to provide prehospital low titer O positive whole blood (LTOWB) to victims of severe trauma in a large geographical area in Southwest Texas.[^10] The University Health System (UHS) San Antonio, a very busy level 1 trauma center reviewed the need for blood in the field by looking retrospectively at its experience with 124 massive transfusion protocol events in a 30-month period with a mortality of 73%. The trauma community found the evidence for the survival advantage of whole blood given as early as possible after the onset of severe hemorrhage was compelling (Alarhayem; Spinella; Strandenes). It was felt that provision of LTOWB in the field could be a means to improve the grim odds faced by such severely injured patients.

STRAC secured a grant for $150,000 from the San Antonio Medical Foundation to fund a collaboration with the South Texas Blood and Tissue Center, UHS and the US Army Institute of Surgical Research/San Antonio Military Medical Center to provide prehospital LTOWB. The program (not trial) provides cold stored low titer Type O whole blood via helicopter EMS (now also with a limited number of ground vehicles in the San Antonio area) to victims of severe trauma and exsanguinating medical patients.

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This program exists because of a number of evolutions of medical thought. The possible barrier from blood banks was lifted by the Board of the American Association of Blood Bankers. They approved a petition allowing low titer group O whole blood as a standard product without need for a waiver and placed no restriction on the amount that could be used. ^[11] A program to identify low titer O positive donors was established in the community (Brothers in Arms: https://southtexasblood.org/brothers) and therefore there was a reliable source for the product. The program is dependent on the logistics management of the blood supply chain. Brothers in Arms participants donate their blood on a scheduled basis, it is deployed to the prehospital field for two weeks and rotated back to the trauma center and other local hospitals during the remainder of the blood unit’s shelf life. This provides efficient utilization. There is a balance of what whole blood is utilized in the healthcare facilities and what donations are available to match this need.

The program provides 2 units each to 18 helicopters and uses the “Mayo Criteria” for transfusion. Women of child-bearing age are not excluded. The blood has a shelf life of 34 days and is actively rotated back to the hospital after 14 days in the field and therefore wastage is reported as quite low. The early reported experience was that in the first 60 days, 32 patients received WB with overall mortality rate of 18.8% and compared to historical control from STRAC level 1 trauma centers this was a 50% reduction. This is not a clinical trial, it has not been reviewed by IRB, but is a clinical pathway as a quality improvement initiative in the provision of care for trauma victims.

Data is being tracked, but will not in its current format be reported as a prospective trial with randomization so the overall success of this approach will likely be assessed with matched controls and by historical comparison with like mechanism and injury scores. An additional facet of this program is novel and worth mention. In anticipation of a mass casualty event such as active shooter or the like, the blood bank has set aside 20 units of WB and administration supplies that are to be delivered to the site of the event. The cost of each unit is reported to be in the neighborhood of $450 with the cost at this time being borne by the EMS agencies. Two other agencies in Texas — Cypress Creek EMS and Harris County EMS in Houston — carry whole blood on their ground ambulances.

There are other efforts to define the role of LTOWB in civilian trauma going on across the world.  The University of Pittsburgh is conducting an NIH R32 pilot project with helicopters flying with whole blood in a clinical trial called the “Prehospital Pragmatic O-WholE blood Resuscitation (PPOWER) using the same inclusion trial as the same institution’s PAMPer trial (NEJM) for prehospital plasma use. This trial is anticipated to provide prospective scientific evaluation of the effectiveness of this therapy.

Is the prehospital use of whole blood for hemorrhagic shock the logical translation of successes pioneered by military medicine or is it another example of an exercise in expensive medical futility that precedes the evidence of benefit in this environment?

Until the evidence is truly available in the next few years, the answer no doubt depends on the lens by which you view it. Critics can cite any number of past episodes in medicine when we were convinced a priori of the value of an intervention or treatment only to later be disappointed. On the other hand, the argument regarding the physiology of hemorrhage, blood and component therapy and the positive experience in a military environment can be viewed as strong support. The National Academies report “A National Trauma Care System: Integrating Military and Civilian Trauma Systems to Achieve Zero Preventable Deaths after Injury” has set the goal of achieving zero preventable deaths from trauma by optimizing all aspects of the system. If we are to achieve that goal, it will certainly require innovation that may outrace the highest quality evidence. As we do so, we may well discover that the therapies do not meet expectations…and some would argue that we cannot afford to wait.