When a bleeding patient is rushed to the hospital, he or she may be injected with a saline solution. But that’s just a stopgap. How scientists are testing blood substitutes that actually work like blood?
When someone loses a lot of blood, emergency responders might not have time to determine the patient’s blood type.
Then the patient can’t receive a blood transfusion until they get to a hospital. Researchers are testing blood substitutes called “hemoglobin-based oxygen carriers.” They contain hemoglobin molecules from recycled human or bovine blood, but they don’t contain the proteins responsible for blood type. So they can be given to anyone.
Ernest Moore is Chief of Surgery and Trauma Services at the Denver Health Medical Center. He has studied blood substitutes for 10 years. He says patient consent is a major challenge.
Ernest Moore: It’s almost an oxymoron, as you can imagine, that if patients are bleeding enough to need a blood product, they probably aren’t conscious enough to have given valid consent. And the frustration for us was that we enrolled literally about 1 out of 12 patients who should be candidates for the study … It took us a year and a half to do a study that we thought we’d get done in two months.
Moore is planning a new trial using a “waiver of consent.” He’ll go to the community at large to get their permission to use blood substitutes, as long as the patient would benefit. Moore hopes the substitutes will win eventual FDA approval.
Sometimes, on the way to the hospital, a saltwater solution is given instead of blood — to buy more time. But saltwater can’t carry oxygen to cells as blood does. And that can be a danger to the patient. According to Dr. Moore, ” if you loose too many blood cells and they’re diluted in the salt water, they can’t carry adequate oxygen to the tissue and therefore you eventually get organ failure or may die because of inability of the body to have adequate oxygen supply.”
Since they have no blood type and are sturdier than fresh donated blood, the new blood substitutes can be carried in ambulances and given to patients in the critical first minutes of care.
Ernest Moore: “We have seen innumerable patients die over the years from lack of red cells. This product, a very simple intervention, may in fact have a very profound effect in improving outcome with patients who have acute blood loss.”
Still, there is more to be learned about the effectiveness and safety of blood substitutes. Moore’s team, along with several others, is just getting started on the third phase of clinical trials on a blood substitute called Polyheme, with hopes of eventual FDA approval.
Here, Dr. Moore talks about how the blood substitute Polyheme is made:
“The product is called Polyheme, and its name is actually descriptive because it is polymerized hemoglobin. The hemoglobin molecule is extracted from outdated blood. Stored red cells can only be kept in refrigeration for 42 days. After that, they are considered ineffective for transport of oxygen.
“The company, Northfield, buys outdated blood from various blood banks around the country. There is apparently an abundant source of outdated blood. That then is sent to their factory and they go through an elaborate process whereby they break up the membrane of the red blood cell, then chemically extract the hemoglobin molecule (the protein that carries oxygen) and then they use a chemical that polymerizes, or incites the combination of, hemoglobin molecules to make it a larger molecule to keep it in circulation longer. Then they purify it and then it’s given back to patients in that form.
“Glutaraldehyde is used to cause the polymerization of the hemoglobin. Once it’s polymerized, then the purification process involves eliminating molecules of hemoglobin that have not polymerized or which have defective polymerization. But fundamentally, they keep purifying until they get a product that’s a polymer of hemoglobin.
“The polymerization increases the half life from roughly 6 hours to 24 hours and in addition to polymerizing it, they add a chemical agent called peroxidate phosphate which increases the unloading of oxygen. It actually decreases the affinity of oxygen so that when it reaches tissue it will be released. So, both increasing the circulating half life of hemoglobin and increasing its transport of oxygen are done with this product.”
Polyheme has recently entered Phase 3 trials for FDA approval. Dr. Moore hopes to treat and study trauma patients who often are in severe shock and cannot give consent. Here he talks about the difficulties with this, and how he and other researchers hope to overcome it:
“[Getting permission from a patient] a huge impasse and that’s really a major barrier to doing acute intervention care for trauma and emergency medicine. Many of these patients come in in a condition in which they are not capable of rendering full consent. [In a former study] we were only successful in one out of 12 patients that would have been candidates. Of every 12 patients that came in that we said, ‘Wow, that’s a perfect patient,’ we could only get consent for one out of 12 of those patients. So it was huge problem – it took us a year and half to do a study we thought we’d get done in two months.
“The pre-hospital trial [the upcoming Phase 3 trial] we’re going to do with ‘Waiver of Consent,’ because we can’t be in the ambulance or the helicopter asking the patient if they want to get a blood product when they are in shock. Getting Waiver of Consent is a huge undertaking, as you can imagine. Waiver of Consent means you do a study where the patient does not give consent because the medical community and the community at large agree that it’s a logical thing to do, that the patient may derive a benefit, and the benefit is greater than the risk.
“The way the Waiver of Consent is procured is a very elaborate process. We must go out into the community and explain to every community group that’s interested why we’re doing the study and what it may mean to them or their loved ones to get involved in the study. We also go to the newspapers and the television news media and are interviewed about the study. We’d probably go to somewhere between 10 and 15 community meetings, and probably go to a couple of the colleges and have open forums.”
More excerpts from an interview with Dr. Moore:
JC: The show that I work on, as I told you before, is really
interested in the work and lives of scientists, so can you tell me
what kind of research you’re doing on blood substitutes right now, or
work you’re doing with the trials that you told me about?
Moore: Well, we have been working with the Northfield Laboratories
for the past 10 years in exploring arenas in which a blood substitute
would be useful for patient care. Our specific interest has been in
the arena of acute trauma. In fact yesterday, delightfully, the FDA
has approved our pre-hospital study. So we are going to be a lead
agency along with 20 centers in the country that are going to
investigate the role of this product in pre-hospital care of the
seriously injured patient.
JC: Are you involved day-to-day in the trials you’ve been telling me
about? I know you had this one that just got approved by the FDA but
you were saying there were some other trials you were doing?
Moore: We have done a number of trials — Phase I and II and IIb,
which means we started out giving this to patients who had minor
trauma to make sure that it had an acceptable safety profile. That
was the first forty patients we used it in. These patients only
required one or two units of blood. And we established that it was,
in fact, safe. And then the next thing we did was look at its
efficacy, specifically we separated out the patients’ blood from the
Polyheme and we looked at how much oxygen there was in the arterial
side vs. the venous side and therefore calculated how much oxygen was
transported to tissues.
Then we set up a trial where we hypothesized that if we used this
product in the emergency department with all patients entering the
hospital, then we would reduce the amount of stored blood they would
require. And this is a very exciting area of research, but certainly
a new one, or I’d say revitalized, because we’ve realized that stored
blood, although recently safe, the longer the storage, the more
adverse the affects are from the product that comes from the blood
bank. Not that blood bankers are doing a bad job, but there is only a
certain stability that blood has under chemical, and artificial
So we hypothesized in this second study that if we gave this agent
instead of stored blood that we ultimately reduce the number of units
of stored blood patients would require during hospitalization, the
benefit then being derived from less confrontation with problems
stored blood has associated with it.
And what we would hope to do, is if we gave injured patients who are
bleeding actively this product that it would be bled out into the
wounds or into the abdomen and therefore not subject the patients to
the risk of the stored blood. Then once we got the bloodletting
controlled, then we would resort to stored blood.
Now, unfortunately, that is complicated by the fact that we had to get consent from these patients to do this. And it’s almost an oxymoron, as you can imagine, that if patients are bleeding enough to need a blood product, they probably aren’t conscious enough to have given valid consent. And the frustration for us was that we enrolled literally about 1 out of 12 patients that should be candidates for the study but couldn’t really legitimately get the consent.
Because of that logistic nightmare, then, we resorted to alternative
hypothesis. The next series of studies we did, we demonstrated both
in basic research in animals and then went to the ICU and showed it
in trauma patients that if we use this product instead of blood under
consent conditions we can actually reduce the amount of systemic
inflammation that stored blood produced.
JC: That’s really fascinating to me, the fact that you had to get
consent. I’m wondering if you can talk a little bit about the
practical… what that was like? How did you get the consent? What
did the family feel like? How do you do something like that when
someone is unconscious or that injured that they could be dying?
Moore: Well that’s the problem with it. It takes a very fortuitous
situation where patients are bleeding at a moderate level but not
severe enough to be in shock. That’s why it took so long. And we also
have the provision here, fortunately, that you can get so-called next
of kin permission, that is, if someone is bleeding and is intubated
and can’t communicate with you and they have a spouse with them, you
can ask the spouse for permission to use the agent.
JC: Now, how did you… I’m just imagining myself if it was one of my
loved ones I think I would be really nervous about trying something
experimental, which seems like a really big conundrum for medical
research, especially in an area that is supposed to help trauma
patients. So, how did you go about initiating that decision, how did
you convince them?
Moore: Well it is a huge impasse. And that’s really a major barrier
to doing acute intervention care for ?? trauma and emergency medicine
— is that many of these patients come in in a condition in which
they are not capable of rendering full consent. The way we achieve
this in this study — and again, as I said, we were only successful
in 1 out of 12 patients that would have been candidates…
JC: You said successful — you mean in getting them to consent?
Moore: Well, no. Of 12 patients that came in that we said, ‘Wow,
these … should the study’ — because we didn’t want overwhelming
blood loss; we wanted to have a situation where most of the blood
would be one or the other in the first 12 hours.
JC: One or the other?
Moore: Either Polyheme or stored blood. That the 12 patients who came in that we said, ‘wow, that’s a perfect patient’, we can only get consent in about 1 out of 12 of those patients. So it’s a huge
problem. It took us a year and a half to do a study that we thought we’d get done in two months.
JC: And how many total patients did you have in the end?
JC: 44. Wow, that’s a lot of people you had to talk to!
Moore: Well, yeah, it got to be such a morass that just — we
couldn’t do it. It was taking forever and it was taking a huge amount of time out to try to do this. We approach the family, like you’re suggesting, and here is some loved one dying in there, and you’re trying to go in the operating room, you’re trying to explain to them you want to give this and what it is and they’ve got to read this and they’ve got to understand the language in it. It’s very difficult.
So to jump to the next one though, the pre-hospital trial we’re going to do with what’s called waiver of consent. Because we can’t be in the ambulance or the helicopter asking a patient whether they want to get a blood product when they’re in shock.
So getting waiver of consent is a huge undertaking as you can imagine.
JC: What does that mean, waiver of consent?
Moore: Waiver of consent means you do a study in which the patient does not give consent because the medical community and the community at large agrees that its a logical thing to do, that the patient may derive benefit and the benefit is greater than the risk.
JC: OK — let’s talk again about the waiver of consent since we left off back there.
Moore: Well the way the waiver of consent is procured is a very elaborate process. We — in fact I met today with a number of individuals in this. We must go out into the community and explain, basically explain to every community group that’s interested why we’re doing this study and what it may mean because it may be them or their loved ones that get involved in the study. WE also go to the newspapers, television news media and are interviewed. In fact, I’ve got about three television interviews set up for the next couple of weeks to talk about the study. And we’re going to run some big ads in both papers — the Rocky Mountain News and the Denver Post about what its all about. And we’re going to probably — I don’t know at this point — we’re going to probably go to somewhere between 10 and 15 community meetings and probably go to a couple of the colleges and have open forums and talk about this. So it’s a very elaborate process.
JC: But it’s basically asking the community to make a decision
together to let you…
Moore: That’s right.