Massive transfusion: a question of timing, detail, a golden ratio

Kevin B. O’Reilly

December 2014—Here it was, the kind of massive postpartum hemorrhage case for which the team at Duke University Medical Center had spent months preparing. The multidisciplinary group had agreed on which laboratory tests would be done in such a case, determined which blood products would be delivered, and decided which members of the OB team would be sent racing to retrieve the potentially life-saving package.

For the two labor-and-delivery nurses designated as runners, the quickest way to get down to the blood bank was the elevator. The elevator was working, but the nurses’ badges did not allow them access to it.

“They had to run all the way down the hall, then all the way down the stairs. It took much longer,” says Evelyn Lockhart, MD, a pathologist who specializes in transfusion medicine and led the Duke team in implementing a massive transfusion protocol for postpartum hemorrhage.

“It was a surprise to us all,” Dr. Lockhart says. Fortunately, the only harm associated with the inaccessible elevator was a couple of winded nurses. That is because the elevator flap came as part of a simulation, and no woman’s life was in danger. It turned out that access to the elevator was restricted to emergency department personnel. That changed soon enough, before any real-life obstetric massive transfusion protocols, or MTPs, were initiated.

The story illustrates an essential truth in the world of massive transfusion, experts tell CAP TODAY. While a randomized clinical trial likely to be published could help answer persistent questions about which blood component ratio can best reduce the mortality rate in massive transfusion cases, experts say that fine-tuning the timely communication, processing, and delivery elements of the MTP are just as essential as determining what “golden ratio” of blood products to prepare.

“[Timing] is clearly important. There’s plenty of data over the years to show it, and it’s a common phrase that every minute counts. In some patients, it doesn’t, but in these patients it really does,” says John B. Holcomb, MD, director of the Center for Translational Injury Research and chief of the Division of Acute Care Surgery at the University of Texas Health Science Center at Houston.

Dr. Holcomb also is principal investigator of the Pragmatic, Randomized Optimal Platelets and Plasma Ratios trial, dubbed PROPPR for short. The 12-center study aims to compare the efficacy of a 1:1:1 ratio of plasma, platelets, and red blood cells with a 1:1:2 ratio of those same components. Half of the 680 patients enrolled were randomized to receive transfusions using the 1:1:1 ratio, while the other half got the 1:1:2 package. The question the trial seeks to answer: Will more plasma save more lives? The primary outcomes are 24-hour and 30-day mortality.

“The rationale for the 1:1:1 ratio is that the closer a transfusion regimen approximates whole blood, the faster hemostasis will be achieved with minimum risk of coagulopathy,” reads the description available at ClinicalTrials.gov (http://j.mp/propprtrial). It says: “The current [Department of Defense] guideline specifies the use of 1:1:1, and this practice is followed on almost all combat casualties. In other observational studies, leading centers have reported good outcomes across a range of different blood product ratios. For example, a 1:2 plasma:RBC ratio is used with little guidance regarding platelets. The proposed randomized trial is intended to resolve debate and uncertainty regarding optimum blood product ratios.”

Because the study’s results were, as of early December, under review for potential publication at a peer-reviewed medical journal, Dr. Holcomb declined to reveal what his research team has discovered. But the study may not settle all the outstanding questions, according to Pampee P. Young, MD, PhD, medical director of transfusion medicine at Vanderbilt University Medical Center. Along with Dr. Lockhart, she spoke at the CAP ’14 session, “Massive Transfusion Protocols in Trauma and Obstetrics,” which drew a standing-room-only crowd.

“I think most trauma surgeons and most transfusion medicine doctors will agree that something greater than 1:2 [fresh frozen plasma] to red cells is important, but whether that’s 2:3 or it’s 1:1 has not been definitively determined, and probably won’t be for a while,” Dr. Young tells CAP TODAY. “[PROPPR] is looking at 1:1 versus 1:2, but I don’t think most people would argue that you need something higher than 1:2. This raises the question of whether 1:2 is sufficient, but it doesn’t answer the question: Could you have a lower ratio?

“Our institution compared, while adjusting by severity of injury, 2:3 versus 1:1 and found no difference,” says Dr. Young, who co-wrote a paper documenting the results involving 211 patients (Cotton BA, et al. J Trauma. 2008;64:1177–1183). “Looking at a historical control, we showed a 74 percent increase in survival. That’s not trivial.”

A  key shortcoming with the previous MTP literature—largely retrospective series—that the PROPPR trial aims to address is that of survivorship bias. Richard M. Kaufman, MD, medical director of the blood bank at Brigham and Women’s Hospital, explains the issue.

“The question is always: Did the FFP transfusions promote survival, or is the FFP transfusion something that happens to patients who survive? The studies have been inherently confounded. That doesn’t mean the idea of transfusing plasma preemptively is wrong. It just means that you have to be cautious in how you interpret the studies,” says Dr. Kaufman, assistant professor of pathology at Harvard Medical School.

For now, Dr. Kaufman and his colleagues at BWH have opted for a 1:1 ratio of plasma to red cells.

“What we have settled on is that we do feel that, in looking over cases in the past, patients really did get behind. They would get a lot of red cells and their clotting factors would get diluted. And by the time the PT and PTT came back, they would have been really hemodiluted, and then it’s hard to catch up.”

“There hasn’t been, really, a large randomized trial comparing lab-directed therapies versus one of these fixed-ratio approaches, and there may never be such a study,” Dr. Kaufman adds. “Anyway, we’re just doing the best we can. . . . It’s really tricky.”

About two-thirds of hospitals with MTPs use a plasma-to-RBC ratio of 1:1 in trauma cases, Dr. Young said during her CAP ’14 talk, summarizing the results of a 14-hospital survey (Young PP, et al. Transfus Med Rev. 2011;25[4]: 293–303). The rest use ratios involving less plasma in differing degrees, just one example of what she characterized as “wide variation” in massive transfusion practice. About half of hospitals use a ratio of red blood cells to platelets that is 6:1 or greater.

More than 60 percent do not routinely use cryoprecipitate, while 15 percent usually give recombinant factor rVIIa. Nearly 70 percent keep thawed AB plasma on hand in the event of MTP initiation, and all hospitals switch to type-specific plasma once that information is obtained, Dr. Young said.

Since 2006, the American College of Surgeons’ Committee on Trauma has required that hospitals seeking trauma center verification have an MTP in place. The 2014 edition of the committee’s Resources for Optimal Care of the Injured Patient states: “Trauma centers of all levels must have a massive transfusion protocol developed collaboratively between the trauma service and the blood bank.”

But the ACS has avoided getting into the nitty-gritty, such as specifying the best blood component ratio for trauma centers to use in MTPs, says Nels Sanddal, PhD. He manages the college’s Trauma System and Verification, Review, and Consultation Program.

“We want them to have one, we want them to monitor it, to see that it’s being initiated appropriately, and we want them to follow up and see if it seems to make a difference,” Dr. Sanddal says. “We’re not being prescriptive about what the particular ratio of blood products is. What we want for them to do is to have one, and use it, and evaluate it.”

When inspecting a trauma center, Dr. Sanddal and his team will ask both the trauma and blood bank teams for their understanding of how the MTP should work.

“We’ll ask the trauma program staff: What do you think you’re going to get when you initiate the massive transfusion protocol? Then we go to the blood bank and say: When you get a call for the MTP, what do you do? What do you scramble, and how do you put it together? How much time does it take? What goes down in the first cooler? What about the second cooler? We try to verify it from both ends.”

Dr. Sanddal says he usually sees a “high degree of concordance,” which appears to speak well of MTP communication at trauma centers across the country.

“The great news is most centers that we visit have one,” he adds. “Whether or not they are initiating that protocol, I can’t guarantee, but they have a protocol in place.”

The life-saving, complication-reducing promise of the MTP does not reside entirely in the blood component ratios transfused, Dr. Young said in her CAP ’14 talk. “The protocolization of the process matters. It’s important to have quality improvement efforts around this,” she said, urging a defined process for how MTPs are started and ended, how unused products get returned, and how cases are reviewed for problems.

Dr. Young noted research done at Stanford University Hospital that compared their experience in the two years before and after instituting an MTP. The hospital did not change its 1:1.8 ratio of plasma to red blood cells before and after, thus allowing for a natural experiment to see what kind of impact the protocol itself seemed to have. Examining patients who needed 10 or more units of red blood cells during their first 24 hours after admission, researchers found a mortality rate of 45 percent among 40 patients in the two years before implementing the MTP. Post-MTP, the death rate fell to 19 percent among 37 patients.