Hello, this is Marty Schreiber coming to you from my office in Portland, Oregon at the Oregon Health and Science University. I am creating a recording that I hope will never be shown because I hope to see you all at the Society of Critical Care Medicine in San Francisco. I've been asked to talk about transfusion of bleeding patients in austere conditions. In the next 10 minutes, I will be talking about walking blood banks, a little bit about liquid cold-stored whole blood, cold platelets, prothrombin complex concentrate, and fibrinogen concentrate. And that's a lot to do in 10 minutes. In terms of disclosure, I am a consultant and grant recipient from both CSL Bearing and Hemanetics, and I am a consultant for Tricol, and that is not relevant. This is the ultimate bleeding patient in austere condition. This is a patient I took care of in Shank, Afghanistan, who sustained gunshot wounds to the abdomen and right popliteal artery. He required a massive transfusion, as you can see on his right chest as recorded. He received one-to-one pack red cells to FFP, two units of cryoprecipitate, and 21 units of whole blood. You see here that he did not receive any platelets. Platelets are not available in austere conditions because they are stored at room temperature for five days and require agitation. This is the most problematic component. The patient's operation is listed on the left side of his abdomen. The Committee on Tactile Combat Casualty Care, which is part of the Joint Trauma System, creates the standards for the care of injured patients in the field. This is the priority list for blood products, starting with number one cold-stored low-titer or whole blood. This was chosen as the first choice because it's FDA approved and can be made readily available in certain locations. Second is fresh whole blood. This is clearly the best product because it provides 100% of all components, as well as additional proteins and all coagulation components that are needed to stop bleeding. Next on the list is plasma platelets and red cells given a one-to-one-to-one ratio, and then one-to-one plasma to red cells, and finally, essentially, whatever you have. So this is based on what's available in your conditions. So who will be a donor in a walking blood bank? What are the characteristics? By nature, this is a low-risk population at low risk for transfusion-transmitted diseases. Their blood types are known and they undergo routine testing every 90 days. They undergo a full transfusion-transmitted disease panel. Their titers to anti-A and anti-B are checked, and anti-HLA antibodies are checked in females. These are the antibodies that cause TRALI. In terms of executing a walking blood bank on-site, the collection site needs to be organized. Standard blood collection forms and materials are utilized. The team that does the collection must be trained and adhere to safety protocols. There needs to be a donor notification mechanism and forward operating bases. This is done through a loudspeaker that yells out, all available donors report to the hospital. This is an example of a walking blood bank that I participated in downrange. You can see a large number of soldiers that will appear very rapidly after notification who are eager actually to give blood. In terms of testing that is done at the time of blood donation, vital signs are checked to make sure they're normal. The patient's hemoglobin is tested. Their blood type and Rh type are confirmed. Rapid testing for HIV, Hep B, Hep C, RPR, malaria are performed on the donated blood, and these tests are 85% sensitive. This is the reason why this process is not FDA approved. In general, an aliquot of the blood is taken and then sent to a lab post hoc for formal testing. Collection is done with standard blood collection bags and tubing, which are properly labeled. A 16 gauge needle is utilized, and ideally a tourniquet is placed on the donating arm and placed at 40 to 60 millimeters mercury. This pressure optimizes the rate of blood donation. The blood donation bag is filled to a line at 450 cc, which is equivalent to 585 grams of hemoglobin. The duration of collection is documented, but should not go over one hour. I'll move on now to cold platelets. Cold platelets enable usage in austere conditions because they can be stored for up to 21 days. So why do we typically use warm platelets? Warm platelets are stored at 22 degrees Celsius in incubators for up to five days, and they are agitated continuously. They can only be stored for five days due to the risk of infection developing. We use warm platelets because in the 1970s studies were done that showed that warm platelets survive longer in vivo and can survive up to four days. Cold platelets will survive in vivo for about 1.3 days after transfusion. 1.3 days is more than adequate in trauma patients because after the acute blood loss stops, functional platelets are no longer as important. In terms of comparing warm versus cold platelets, regardless of the test that is performed, cold platelets are more activated and more functional and more efficient at causing clot formation. And this data was really nicely shown in the studies by Reddick and have been repeated in studies by Andre Kapp as well. Cold platelets have been tested in a randomized study. This study was performed in Norway on cardiothoracic patients. And this slide looks at the utilization of blood products comparing randomized patients who receive either room temperature patients stored up to seven days, cold stored platelets up to seven days, or cold stored platelets up to 14 days. And as you can see, regardless of the platelet type, the amount of blood component utilized was the same whether it was red cells, plasma, or platelets. Cold platelets are stored in theater for up to 21 days. Next I'll talk about prothrombin complex concentrate. This is a concentrate made from combined human plasma. Thousands of donors' plasma are mixed and then turned into a complex, which is concentrated. It contains the procoagulant factors 2, 7, 9, and 10, as well as the anticoagulant protein CNS, antithrombin 3, and heparin. There are 200 additional protein present in prothrombin complex concentrate, some of which we know the function and some we do not. The dose is generally between 25 to 50 units per kilogram, and PCC is approved for urgent reversal of patients on Coumadin who are bleeding or require emergency surgery. This is based on a well-done randomized trial in patients who are on Coumadin and require either emergency surgery or were bleeding. These slides show that when four-factor prothrombin complex concentrate is utilized, correction of coagulopathy is extremely rapid, especially when compared to plasma. And this is shown in two different forms with the same results. The same is assumed to be true in trauma patients with trauma-induced coagulopathy, that they would have a much more rapid correction of coagulopathy with PCC. This has been studied in large-scale trauma studies based on the Trauma Quality Improvement Project from 2015 to 2016. Patients in TQIP were propensity score matched so that two equal populations were addressed. 486 patients were studied, 243 patients received FFP alone, and 243 patients received FFP plus four-factor PCC. The results of the study showed that in the patients who received PCC in addition to FFP, the PAC red cell utilization was lower, plasma utilization was lower, both at four hours and at 24 hours. Also overall in-hospital mortality was lower. Interesting as well, looking at complications, the instance of acute kidney injury was lower in the patients who received PCC as was the instance of ARDS, and the mean median hospital length of stay was also lower. Next I'll move on to fibrinogen concentrate. These concentrates are very important in Oster conditions because they are stored at room temperature and can be stored for a prolonged period of time and then rapidly re-concentrated. Fibrinogen concentrate comes in a concentration of about one gram in 50 milliliters, which is similar to cryoprecipitate and much more concentrated than FFP. Fibrinogen concentrate is virally inactivated by pasteurization as an additional purification that removes both antigens and antibodies, decreasing the risk of allergic reactions. The RETIC trial, which studied early use of fibrinogen concentrate compared to FFP was a single center, open label, randomized trial that randomized people between the ages of 18 and 80 with injury severity score greater than 15. Patients with coagulopathy as measured either by fibrinogen dysfunction or prolonged clotting time were enrolled in the study. Repeat dosing was based on the results of the repeat ROTEM. The initial dose of FFP was 15 milliliters per kilogram, or patients received fibrinogen concentrate at a dose of 50 milligrams per kilogram. Redosing was a major aspect of this study. And the study was actually stopped early because the FFP group at interim analysis was shown to require salvage much more frequently than the fibrinogen concentrate group. These graphs show the result of the study. Fibrinogen concentrate is in blue and FFP is in yellow. On the x-axis is a bleeding score, which the group used to look at patients who had ongoing bleeding. What you see here is patients with a bleeding score of zero were more likely to have received fibrinogen concentrate, whereas patients who had very high bleeding scores and were continuing to bleed were more likely to receive FFP initially. Furthermore, shown in the graph here below, patients who received fibrinogen concentrate were less likely to undergo a massive transfusion than those that received FFP. And these scores are correlated with the bleeding scores. Furthermore, looking at the number of doses required to obtain hemostasis, patients were much more likely to receive a single dose if they received fibrinogen concentrate than if they received FFP. Next, I'll talk about TXA, which is used as an adjunct to stop bleeding. I won't discuss at this time the CRASH-2 trial. It is somewhat controversial, but the much more recent STAMP trial that was a prospective randomized multi-center trial performed in four trauma centers in nearly 1,000 patients. Patients that were randomized to TXA received one gram in the field versus a placebo, and then there were three additional randomizations after arrival to the hospital, which were no additional TXA, one gram over eight hours, a second one gram bolus, plus a one gram infusion. Looking at all patients in this study, there was no survival difference in the tranexamic acid patients compared to the placebo patients. However, looking at a subgroup analysis, it turns out that patients who received TXA in less than an hour did have a survival advantage, as well as those that were severely hypotensive with systolic blood pressure less than 90. This patient population has a very high mortality and provides a group that can be studied to really look at the efficacy of agents that stop bleeding. Finally, I'll just very briefly mention dry plasma. This is lyophilized plasma. This is powdered plasma, is logistically superior, it can, again, be stored for a very long period of time and can be rapidly reconstituted. There are two major types of lyophilized plasma that are currently being used in the world. The German lyoplas is a single donor plasma. This is widely used throughout Germany and is routinely used in their hospitals. This does require compatible blood types. The French Flip-P, on the other side, is up to 11 donuts per unit, it's a multi-donor product, it is pathogen reduced, and it can be used in any blood type without concern of transfusion reactions. The French Flip-P, in randomized trials, has been shown to result in more rapid elevation of the fibrinogen, and it is available to U.S. Special Forces on an IRB protocol. So in summary, this is an example of what today's Special Forces medics are carrying in their backpacks. Today's Special Forces medics carry liquid cold-stored whole blood. It is not luke-reduced and can be stored for up to 35 days. It is low-titer and type O. They also carry the cold-stored platelets, which are generally not available in theater otherwise, and they do carry lyophilized plasma. In many ways, this backpack-carried blood bank is better than some level 1 trauma center.

transfusion

austere conditions

walking blood banks

cold platelets

prothrombin complex concentrate