On a busy spring afternoon, an overhead call for a “code transfusion” stirs commotion in the trauma bay at Toronto’s St. Michael’s Hospital. Immediately, two units of blood are loaded onto the “rapid transfuser.” Within minutes a cooler arrives from the blood bank containing more blood and thawed plasma.
This is the standard of care for a critically bleeding patient in most academic hospitals and has been proven to save lives. The risk of dying from bleeding depends on how fast patients are treated. The closer to advanced interventions, the better the chances of survival. Yet, it’s a standard that cannot be easily replicated in remote settings.
Now, however, new blood products are available to help bridge that gap.
Some rural centres in northern communities may only have four units of blood available to them; replenishing that supply can take days. Even where limited plasma is available, it needs to be thawed before administration, delaying treatment. This scarcity of invaluable blood resources combined with competing priorities means that in resource-limited settings, patients are deprived of important interventions until transfers can be arranged.
“As far as I am aware, many rural centres do not have a massive hemorrhage protocol,” explains Victoria Myers, a fifth-year Emergency Medicine resident in the University of Toronto FRCP program. She has divided her final year of specialty training between working in state-of-the-art trauma centres in Toronto and remote rural communities like Sioux Lookout and Moose Factory. “There’s a great desire to conserve blood products and resistance against releasing universal type O blood. And if you want specific blood components like plasma and platelets, you have to specifically ask for them.” And even then, they may not be available.
Life-threatening bleeding is a rare presentation but when it occurs – whether it be in a trauma victim, a gastric bleed or a birthing mother – the early minutes and hours are of great importance.
“We know that early blood instead of saline has survival benefits,” says Myers. “And the earlier the better. Yet remote northern nursing stations have no blood so patients who arrive there get saline until a transfer helicopter arrives.”
Logistics complicate the availability of conventional blood products in remote settings. Massive transfusion protocols are resource intensive. They require dedicated staff, training and, most importantly, blood products that are hard to maintain, have a short shelf life and are difficult to administer. More stable and logistically sound blood products have become available in recent years, paving the way for more equitable care.
“The way we think about this resuscitation paradigm is that the first thing you want to do is stop the bleeding in the prehospital environment as much as you can,” says Andrew Beckett, trauma medical director of St. Michael’s Hospital. He sees blood and blood products as a bridge to the definitive management patients need: surgery. “You use freeze-dried plasma [if available] as a bridge to whole blood or balanced blood component resuscitation, which is the bridge to damage-control surgery. So, these things are all bridges to each other. And if one bridge is broken, then, you’re not going to get to the next one.”
Lawrence Bruce Robertson, a Canadian physician, first described the survival benefits of arm-to-arm transfusion among First World War casualties. At the time, this was a significant deviation from the standard of administering saline (salt water) or glucose (sugar water) solutions. Later, during the Spanish Civil War, a primitive Blood Transfusion Service was set up to deliver whole blood units to the frontline and casualty collection stations. Then, during the Second World War, Canada played a significant role in providing allied forces with freeze-dried or lyophilized plasma.
In the 1970s and 80s, component therapy with red cells, plasma, platelets and cryoprecipitate was adopted. This remained the favoured approach until the HIV epidemic and HCV outbreaks put a damper on the enthusiasm for resuscitation with blood products, leading to greater endorsement of crystalloid fluids, solutions of salt, water and minerals. It wasn’t until the Afghanistan and Iraq wars that blood and balanced blood products came back into prominence. More recently in the 2010s, the U.S. military began using fresh whole blood as the resuscitation fluid of choice.
“A lot of what we’re doing now is just rediscovering what we’ve learned from the past,” asserts Beckett.
Among those lessons is the resurrection of freeze-dried products, including fibrinogen concentrate, prothrombin complex concentrate (PCC) and freeze-dried plasma. Compared to their first-generation ancestors, these products are purified, and pathogens reduced. Moreover, compared to conventional blood components, they are easier to administer, have a longer shelf life and in some cases do not require refrigeration. Additionally, wastage is reduced given their powder form, more durable containers and easier storage conditions.
Luis Da Luz, a trauma team leader at Sunnybrook Hospital, is the lead investigator for the FIRST II trial to determine if replacing conventional products with fibrinogen concentrate and PCC improves patient outcomes. He says that if these products perform the same as conventional components, and no harm is revealed, their logistic advantages can open new doors to treatment in remote and rural settings.
“In remote settings, often access to plasma is delayed,” says Da Luz. “Even if plasma exists, it’s frozen and thawing takes about 30 minutes. Then there is the risk of viral transmission which, although very rare nowadays, still exists given the possibility of new, emerging pathogens.
“But something like fibrinogen concentrate can be stored at room temperature and reconstituted in a couple of minutes, giving you a fixed dose of the medication. Also, the risk of lethal transfusion complications, even though rarely seen with conventional blood components, are eliminated.”
“Those will be the game-changers in getting patients to trauma centres for definitive care.”
Recently, the Canadian Blood Services and the Canadian Armed Forces have begun working on developing freeze-dried plasma products that, Beckett says, “are stable at room temperature for two years and mix up within 90 seconds. So, if you think about it as a bridge to whole blood, together those will be the game-changers in getting patients to trauma centres for definitive care.”
Although freeze-dried plasma is available in Europe, it has yet to receive Health Canada approval. But PCC and fibrinogen products have made their way to clinical guidelines based on available evidence. The Ontario Regional Blood Coordinating Network (ORBCON) recommends that “at institutions lacking sufficient resources to issue plasma (e.g., no thawing device or no plasma stocked in inventory), Prothrombin Complex Concentrates can be substituted for coagulation factor replacement and Fibrinogen replacement should be given concurrently with PCCs.”
However, not many institutions have implemented this recommendation.
“The provinces pay into the costs of Canadian Blood Services, and then all medical facilities get blood products free of charge. So, it doesn’t cost the hospitals. They have Health Canada approval and are recommended by ORBCON,” says Beckett. “There’s no reason for products like fibrinogen concentrate and PCC not to be available. The local medical advisory committees and local leadership have to decide they want to do this.”
Myers points to a lack of institutional knowledge as an obstacle.
“In order to have a massive hemorrhage protocol, you need to have a physician that is going to design it, implement it, lead the education, lead the lab in,” she says. “And most of these hospitals are run by extremely hardworking, rural family physicians with a broad range of practice, most of whom work there transiently and are faced with a lot of competing priorities. And then the number of times they need a massive hemorrhage protocol is exceedingly less than huge downtown centres. So, there is not a lot of institutional initiative.
“Without a clear pathway policy, like a simple infographic of how and when to give these blood products, I think even if they [blood products] were in the centres, they would not get used.”
Freeze-dried products could be a significant boost to the “blood-on-board” program launched by Ornge, Ontario’s air ambulance and critical care transport service. Ornge began a “blood-on-board” program in 2021 and is expanding it to northern Ontario this year, putting universal blood on board and allowing paramedics to launch without delay to bring blood products to communities across northern Ontario.
“Unfortunately, geography plays a big role in your access to care across the province and the country,” says Brodie Nolan, a trauma team leader at St. Michael’s Hospital and a Transport Medicine Physician with Ornge. “We know that bleeding is a time-sensitive event and just by the challenges of being further away you’re going to run into longer times.”
Nolan says prehospital use of blood products or blood components is a way to mitigate this risk: “Blood is a scarce resource. It’s just impossible to stock all hospitals with all the components. We just don’t have enough.”
He points to the logistic limitations of conventional components: “When we take our in-hospital transfusion practices and apply that to an out-of-hospital transfusion practice, like onboard an aircraft, we have to think about things like weight, you have to think about things like weather. We can keep red blood cells in a temperature-controlled cooler and replace our supply every couple of days.” But stocking plasma is more complicated, needing specialized equipment and possibly creating a lot of waste. “So, seeing something like a freeze-dried plasma or that type of product would be a huge benefit. Because you have something that’s temperature stable, and you don’t have to switch it out every couple of days.”
Beckett agrees: “In Canada, we live in a tyranny of distance. To get somebody down from James Bay can take more than six hours. Can you keep somebody going for six hours? That’s difficult to answer but with different adjuncts, and at least by delivering blood products on the evacuation platforms, there’s a chance of buying the person time to get to a facility where they can be handed over.”
Nonetheless, there remain hurdles to bringing freeze-dried products to remote settings. First and foremost is cost and cost benefit. Critical bleeding is a rare phenomenon and introducing products that caregivers aren’t familiar with requires a substantial educational campaign. Then, there are concerns about supply. “For some of these products, like fibrinogen concentrates,” says Beckett, “we collect the plasma in North America, and then ship it to Europe for fractionation. Canada only has the fractionation capability to meet maybe about 20 per cent of our domestic needs. This exposes us to supply-chain shocks.”
Additionally, evidence supporting use of these products in the prehospital setting, although promising, is not robust.
“We don’t know which exact patients benefit from these interventions. And I think that’s part of the issue,” Beckett adds. “We saw [the benefit] in retrospective military studies. This is a different patient population than the civilian population, with a different mechanism of injury, and a different evacuation system. So, the large survival benefit doesn’t necessarily translate into civilian prehospital care models.
“But regarding the question of whether we should have more accessible blood products for patients who may benefit in remote and Indigenous communities? For sure. And should we have those products on aeromedical platforms? I think that’s reasonable and doable.”