http://www.popsci.com/popsci/science/9e367f36fca9e010vgnvcm1000004eecbccdrcrd.html
Better Than Blood?
Nicole Davis
Grace LeClair had just finished eating dinner
with friends when she got the phone call every
parent dreads. The chaplain at the Medical
College of Virginia was on the other end. Your
daughter has been in a serious accident. You
should come to Richmond right away. LeClair was
in Virginia Beach at the time, a two-hour drive
from 20-year-old Bess-Lyn, who was now lying in a
coma in a Richmond hospital bed.
The friend who was with Bess-Lyn has since filled
in the details of that day in March. The two
women were bicycling down a steep hill, headed
toward a busy intersection, when Bess-Lyn yelled
that her brakes werent working and she couldnt
slow down. Her friend screamed for her to turn
into an alley just before the intersection. But
Bess-Lyn didnt turn sharply enough and crashed,
headfirst, into a concrete wall. She wasnt
wearing a helmet. By the time the ambulance
reached the hospital, Bess-Lyn was officially
counted among the 1.5 million Americans who will
suffer a traumatic brain injury (TBI) this year.
Bess-Lyns mom was halfway to Richmond when she
received a second call, this time from a doctor.
He was telling me that she had a very serious
injury, that she had to have surgery to save her
life and that if I would give permission, they
would use this experimental,
not-approved-by-the-FDA drug, Grace LeClair
recalls. He said that it would increase the
oxygen supply to her brain. To me that only made sense, so I said yes.
With her mothers verbal consent, Bess-Lyn was
treated with a type of artificial blood called
Oxycyte, the subject of a clinical trial led by
doctors at the teaching hospital of Virginia
Commonwealth University. In animal tests, the
compound has been proven to cut the effects of
brain damage nearly in half, presumably because
its tiny particles can ferry oxygen through
swollen, injured vessels our own red blood cells
cant squeeze through. (The suffocation of brain
cells is a major contributor to brain damage.)
The doctors next step is to get the same result
in accident victims like Bess-Lyn, who became the
third of eight patients to be enrolled in the
hospitals pilot Phase II clinical trial,
designed to test the drugs safety and efficacy.
If Oxycyte performs well in subsequent trials, it
will become the first drug the FDA approves to
treat traumatic brain injury in the U.S. and in
hot spots like Iraq, where TBI has become horrifyingly common.
THE RED AND THE WHITE
Oxycyte is the newest product in a family of
compounds known as artificial blood. The search
for a synthetic substitute for human blood began
at least as early as the 19th century, when
doctors actually tried using milk to replenish
blood loss. With the onset of the AIDS crisis in
the early 1980s, pharmaceutical companies took on
the cause in force, competing to create an
artificial substance that could eliminate the
problemsincluding tainted blood and supply
shortagesassociated with donated blood. The idea
was that these substitutes could replace the use
of donated blood in transfusions, during surgery,
and in patients who had experienced major blood loss through injury.
Two categories of contenders soon emerged. The
first was a red-colored substitute made in part
from human or animal hemoglobin, the protein in
our red blood cells that carries oxygen. The
second was a snow-white, completely synthetic
substance made from perfluorocarbons, or PFCs, a
compound whose chemical makeup closely resembles
the nonstick Teflon in your frying pan. PFCs have
the highest gas-dissolving capacity of any liquid
and, when used with supplemental oxygen, allow
blood to carry many times more oxygen than it
normally does (and to carry more oxygen faster
and more easily than hemoglobin-based substitutes).
In large-scale clinical trials in the 1980s and
1990s in which researchers pitted the fake bloods
against the real thing, patients who received the
artificial stuff experienced a disproportionate
number of heart attacks and strokes. Those
outcomeswidely attributed to a combination of
poorly designed trials and first-generation
formulationseffectively shut down human studies
and, in some cases, bankrupted biotech firms.
After two decades and a billion dollars worth of
research, the most valuable lesson learned was
that real blood and these artificial bloods were
apples and oranges: The life-giving liquid in our
veins acts like a supply line for everything from
nutrients to hormones to oxygen, even working
double-time to regulate our blood pressure and
fight infection. The manufactured substances, on
the other hand, are one-trick ponies for oxygen
delivery. But its a trick they perform
remarkably wellin the case of PFC-based
substitutes, carrying oxygen at rates roughly 50 times that of our own blood.
Today, blood substitutes are often called oxygen
therapeutics for this very reason, and
manufacturers are no longer putting them up
against real blood in clinical trials. In fact,
sophisticated screening practices have made
donated blood so safe that finding an alternative
to diseased blood is no longer necessary. But
there is still a significant need for a
universal-type, oxygen-carrying fluid,
particularly as a solution to ever-more-common
shortages of donated blood and as a fool-proof
substitute for the military, which poured at
least $10 million into developing a blood proxy
before giving up and waiting for pharmaceutical
companies to solve the problem for them.
Doctors at VCU are betting that a successful
pilot trial of Oxycyte will win the attentionand
influenceof the armed forces, which would help
usher the drug through the clinical-trial process
and into the hands of doctors and medics in the
near term. At least thats the hopeor rather,
the careful, calculated planof Bruce Spiess.
DR. BLOOD
Spiesss office, #007, is in the basement of a
building not far from the ER where Bess-Lyn was
rushed after her accident. Stuck among a bunch of
animal laboratories along a cinder-block hallway,
the office is far less prominent than you would
expect for someone in charge of a major research
center. Along with two other physicians, Spiess
heads the Virginia Commonwealth University
Reanimation Engineering Shock Center. Formed in
2000, the institute, which goes by the acronym
VCURES, comprises some 50 scientists, engineers
and doctors, all focused on developing treatments
for traumatic injury. VCURESs research dovetails
perfectly with the needs of the military; its
current projects include an implanted sensor that
could detect the severity of a soldiers wounds
on a battlefield and a kitty-litter-like compound
that could quickly stop bleeding from an open
wound. Artificial blood, however, is perhaps
VCURESs most ambitious project. And artificial
bloods most dedicated advocate at VCURES is Bruce Spiess.
For years, the anesthesiologist has advanced
ideas that seem downright heretical, ranging from
his stance that traditional blood transfusions
usually cause more harm than good, to his
beliefreached before most in the industry that
blood substitutes should not actually be used in
place of blood. I realized very early on that
going head to head with a unit of blood was going
to be difficult, Spiess, 52, says from behind
his cluttered desk. Instead, why not take these
compounds, understand how they deliver oxygen to
tissues better than blood stored from a bank, and
use that as a real advantage. Go find some
diseased states to treat that, right now, we
dont have a treatment for. He leans back in his
chair and smiles, as if this last point is so
obvious he cant believe hes still making it.
It was during Spiesss final year of
anesthesiology training, in 1982, that his
professor at the Mayo Clinic asked him to compile
a summary of the three blood substitutes created
up to that point. Two of them were made with
PFCs, and Spiess found those two particularly
intriguing. Developed in the 1940s during the
Manhattan Project to stabilize highly reactive
uranium isotopes, PFCs are completely inert oils.
Like Teflon, almost nothing sticks to them, which
is why they must be emulsified before they can be
soluble in blood. These chemists were working on
trying to blow things up, Spiess says. It was
just by luck that they eventually noticed that
these liquid PFCs carried huge amounts of oxygen.
Now, more than 20 years after he first studied
artificial blood, Spiess has worked with nearly
every substitute ever made. Bruce was one of the
first and best academic people in this field,
says Robert Winslow, the former head of the
Armys now-defunct artificial-blood program. He
was one of the first people who said, This isnt
just blood; thats way too simple. These
solutions have to be thought of as therapeutic
agents in and of themselves. In the past two
decades, Spiess has been involved in overseeing
more than a dozen human and animal studies, both
of hemoglobin-based and PFC-based blood
substitutes. Manufacturers routinely approach him
for advice and invite him to conduct research on
their productsas did Synthetic Blood
International, the maker of the PFC Oxycyte. In
late 2005, Spiess teamed up with noted VCU
neurosurgeon Ross Bullock to design the Phase II
pilot trial (Bullock had earlier conducted
successful animal studies with the drug). The
trial, Spiess says, is the first step in
determining whether Oxycyte will ultimately be
adopted to treat a wide array of injuries,
including traumatic brain injury, which affects
everyone from car-accident victims to pummeled
boxers to bicyclists like Bess-Lyn. Aside from
giving patients oxygen and anti-inflammatories
and, in extreme cases, removing part of the skull
to release the pressure of the swelling brain,
there are few treatments for TBIand no drug
therapy. Which is precisely why Spiess has chosen to focus on it.
The FDA is in some ways pressured, because one,
theres not a good treatment for brain trauma,
Spiess tells me, explaining his strategy for
getting the agency to pay attention to a drug he
thinks will fill a critical void in emergency
medicine. Two, theres a major international
event going on, and were losing our soldiers
because of brain trauma. Traumatic brain injury
is now found in 30 percent of the injured
veterans sent home to Walter Reed Army Medical
Center from Iraq and Afghanistantwice the
percentage as in Vietnam. Often caused by the
concussive force from insurgents improvised
explosive devices or from penetrating head
wounds, TBI can wipe out a victims memory, leave
him blind, trigger epilepsy, or kill him
outright. Many are calling it this wars
signature wound. So its no coincidence that the
Army and Navy have expressed interest in the use
of Oxycyte to deliver oxygen to the brain.
Getting the military on board, Spiess says,
improves the chance of getting the drug on a
fast track, the sped-up FDA approval course
that could put Oxycyte in Iraq by late next year.
If we can get it through the FDA, then we can
use it in so many different ways, Spiess says.
To treat stroke, for instance, or heart attacks,
sickle-cell anemiaeven spinal-cord injuries."
SPINAL ZAP
Jason Highsmith leads me into a cold,
fluorescent-lit room filled with half a dozen
rat-size operating tables. Recently, Highsmith, a
neurosurgeon who just finished his residency at
VCU, inflicted spinal-cord injuries on sedated
animals and then tried to increase oxygen flow to
the impacted areas using Oxycyte. Studies have
shown that preserving as little as 5 to 10
percent of the neurons in the spinal cord after
an injury can mean the difference between being
wheelchair-bound and walking with a cane. Keeping
the oxygen flowing is vital to those neurons survival.
Its like a magnet for oxygen, says Highsmith,
33, who is 6'2" and bean-thin. He hands me a
leftover glass vial of Oxycyte from the fridge,
half-filled with the white fluid whose watery
consistency reminds me of soymilk. It doesnt
look like much, but when combined with
supplemental oxygen, the amount of Oxycyte in a
jar the size of an aspirin bottle can carry as
much oxygen as the four liters of blood typically
pumping through a persons body.
Highsmith offers me a seat beside his computer
and pulls up a PowerPoint presentation. I just
shared this with the neurosurgery department last
night, he says, still sounding keyed-up. To
explain why Oxycyte is so beneficial during
injuries, Highsmith clicks through to an image of
a healthy human spinal cord. A forest of
microcapillaries branches around it, each
microcapillary three or four microns wide. To
deliver oxygen, our doughnut-shaped red blood
cells, which are naturally wider than those
capillaries, must nonetheless squeeze through the
tiny passageways to unload their oxygen. Theres
not a lot of room for error, Highsmith says,
even under normal circumstances.
Once the spinal cordor any organis injured,
these incredibly narrow vessels constrict even
further, a reaction some researchers believe must
be the bodys way of preventing blood loss. The
defense mechanisms unfortunate side effect is
that it starves the damaged tissue of oxygen
until the veins collapse and, in extreme cases,
the tissue dies. Highsmith clicks to a picture of
an injured human spinal cord, and it looks as if
the once-thriving forest of veins has been
clear-cut. He assumes that the rats that received
PFCs in his study maintained a healthy grove of
veins even after injury, since the oxygen levels
in their spinal cords were six times as high as
in the rodents that didnt get Oxycyte. Its
like a miracle drug, he says. Like pouring oxygen over the tissues.
BUYING SYNTHETIC
A wonder drug, perhaps, but one with caveats.
Most of those in the artificial-blood world, like
Steven A. Gould, the CEO of Northfield
Laboratories in Evanston, Illinois, have hedged
their bets on the more common hemoglobin-based
substitutes. Northfields PolyHeme, for instance,
has recently completed its last clinical trial;
the company is now compiling its data for the FDA to review.
The benefit of hemoglobin-based oxygen carriers
is that oxygen is loaded onto them when were
breathing room air, Gould says. That is,
hemoglobin-based substitutes work just like our
own blood. To get the full effect from Oxycyte,
on the other hand, a patient breathes in 50 to
100 percent oxygen four hours before receiving it
and for 12 hours after its infused (air contains
21 percent oxygen). Thats a logistical
limitation, Gould says, and in general, its
preferable not to breathe supplemental oxygen if it can be avoided.
Most of todays ambulances carry oxygen on board,
as do military rescue helicopters, so the problem
isnt getting a tank of air to the patient. Its
the risk of inhaling supplemental oxygen for too
long. Scientists know that pure oxygen increases
the number of free radicals in our bloodstream,
which can damage tissues and membranes, but the
long-term severity of that damage is unknown.
Spiess believes that Oxycyte could still work at
even lower levels of oxygen, or even with room
air, but he hasnt yet been able to test out
either of those scenarios on humans.
And there are other, undeniable side effects. In
past PFC studies, patients were found to
experience a transient swelling of the liver as
it absorbed the oily molecules of the PFC; some
patients demonstrated a decrease in platelet
count, which can hinder the bloods ability to
clot; and some suffered short-term flu-like
effects. Spiess has a quick response to concerns
like these: If youve been hit in the head or
youve been shot or youre having a stroke, you
dont sweat the flu-like symptoms. All drugs
have some measure of toxicity, Spiess says. Its
simply a case of the good outweighing the bad.
Although the sample size is far too small to be
statistically definitive, it seems that VCURESs
brain-injury trial may be an example of just
that. By August, the hospital had enrolled all of
the eight patients it needed to complete the
Phase II study. Even at the best trauma centers
in the world, the mortality rate for TBI victims
is one in three. Of the eight patients Spiess and
Bullock treated with Oxycyte, only one died. The
recovery process for the surviving patients has been unusually smooth.
Extraordinarily so, in Bess-Lyns case. After
regaining consciousness two weeks after the
accident, she recovered movement in her paralyzed
right side and was ultimately deemed well enough
to leave rehab a week earlier than predicted. She
is expected to make a full recovery. Meanwhile,
Spiess and Bullock are busy designing a larger
trial that will bring their oxygen therapy to
emergency rooms across the countryperhaps as soon as next year.
Nicole Davis is a journalist based in Brooklyn.
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