The large Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was supposed to provide a definitive answer for which ratio is safer and more effective: infusion of trauma patients with blood products in a balanced 1:1:1 ratio of plasma to platelets to red blood cells (RBCs) or a 1:1:2 ratio.
Instead, the study left many emergency physicians with new questions. Its sample size of 680 patients from 12 North American Level I trauma sites was powered to detect an absolute 10 percent difference in mortality between the two arms at 24 hours, an endpoint it did not meet. No significant difference in mortality was seen between the two arms at either 24 hours or 30 days, nor were there any significant differences in any of 23 pre-defined adverse events or functional status at discharge. (JAMA. 2015;313:471.)
But a preplanned analysis of the data revealed some important differences. Hemorrhagic death significantly decreased in the balanced ratio group (9.2%) compared with the 1:1:2 group (14.6%, p=0.03), and significantly more patients also achieved hemostasis in the 1:1:1 group (86% vs 78%; p=0.006).
“To my knowledge, this is the only nonsurgical intervention that has ever significantly decreased hemorrhagic death in trauma patients,” said the study's lead author, John Holcomb, MD, the vice chair, a professor, and the chief of the acute care surgery at the University of Texas Health Science Center at Houston Medical School and the director of the Memorial Hermann Texas Trauma Institute. “At the same time, it did not worsen any inflammatory complications or lead to any increase in head injury death. People had been very concerned that the 1:1:1 ratio, with its extra plasma and platelets, could cause a great increase in inflammatory consequences, and we did not see that at all. This is clearly a safe intervention, and decreases hemorrhagic death.”
Because of the study's parameters, it was not possible to separate out those patients with an unsurvivable brain injury (23% of deaths at 24 hours; 38% of deaths at 30 days). “The study required patients to be enrolled very rapidly in the ED — patients were enrolled within eight minutes of arrival,” said Dr. Holcomb. “So we were unable to get CT scans, and TBI and hemorrhagic shock can look exactly the same. Because of that confounding effect, there was no difference in the primary endpoint, but the pre-specified endpoint of hemorrhagic death had a clear difference.”
Physicians at the University of Texas Health Science Center at San Antonio have been using the 1:1:1 ratio ever since PROPPR's predecessor, the Prospective Observational Multicenter Major Trauma Transfusion (PROMMT) trial, also led by Dr. Holcomb, was published in JAMA Surgery two years ago. (2013;148:127.) That study found that higher plasma and platelet ratios early in resuscitation were associated with decreased mortality. Patients with ratios less than 1:2 were three to four times were more likely to die in the first six hours than patients with ratios of 1:1 or higher.
“If you look at the number-one reason people die from trauma, it's hemorrhage,” said Salim Rezaie, MD, an associate clinical professor of emergency and internal medicine at the University of Texas Health Science Center. “This study shows that the 1:1:1 ratio leads to a lesser proportion of people bleeding to death, so it's a reasonable strategy to go with 1:1:1.”
But there's a caveat, of course. The two arms of the study were not exactly alike. The 1:1:1 group received platelets first, then red blood cells and plasma, while the 1:1:2 group received red blood cells, then plasma, then infused platelets. “Is it the 1:1:1 ratio, or is it the order of products that made a difference in hemorrhagic death?” asked Dr. Rezaie. “That's frustrating. Which was the determining factor? But regardless, there is no increase in harm from the 1:1:1 protocol. I just don't know what order to tell people to infuse the products based on this study,” he said. “PROPPR was both a platelet and a plasma study, and the two are inseparable when dealing in a pragmatic fashion with bleeding patients.”
With the release of the PROPPR trial, Dr. Rezaie said his center has switched its 1:1:1 order from RBCs first to platelets first. “Taking all the evidence together, it looks like 1:1:1 with platelets first has less bleeding associated with it.”
“It is an important question about the order of products,” acknowledged Dr. Holcomb. “You can only study so many factors in one experiment. I can't say that if we'd changed the order of platelets, it would have affected the outcome or not. But my bias is that early platelets seem to be beneficial.”
The next step, Dr. Holcomb said, is moving blood product infusions to the prehospital setting. “Right now, we have an ongoing prospective observational study at nine centers throughout the United States evaluating the effect of red blood cells and plasma infused on helicopters.” That study began in January, and had enrolled 500 patients as of early June. “We're also talking with two ground units here in Houston about getting the products into EMS.”