Better Than Blood?
A man-made, pure-white compound called Oxycyte carries oxygen 50 times as effectively as our own blood. Researchers are betting that itâ€™s the best way to treat Americaâ€™s leading cause of accidental death: traumatic brain injury
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 weren’t working and she couldn’t slow down. Her friend screamed for her to turn into an alley just before the intersection. But Bess-Lyn didn’t turn sharply enough and crashed, headfirst, into a concrete wall. She wasn’t 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-Lyn’s 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 mother´s 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 can’t 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 hospital’s pilot Phase II clinical trial, designed to test the drug’s 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 problems–including tainted blood and supply shortages–associated 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 outcomes–widely attributed to a combination of poorly designed trials and first-generation formulations–effectively 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 it’s a trick they perform remarkably well-in the case of PFC-based substitutes, carrying oxygen at rates roughly 50 times that of our own blood.
by John B. Carnett
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 attention-and influence-of 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 that’s the hope–or rather, the careful, calculated plan-of Bruce Spiess.
Spiess’s 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. VCURES’s research dovetails perfectly with the needs of the military; its current projects include an implanted sensor that could detect the severity of a soldier’s wounds on a battlefield and a kitty-litter-like compound that could quickly stop bleeding from an open wound. Artificial blood, however, is perhaps VCURES’s most ambitious project.And artificial blood’s 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 belief-reached 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 don’t have a treatment for.” He leans back in his chair and smiles, as if this last point is so obvious he can’t believe he’s still making it.
It was during Spiess’s 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.
by John B. Carnett
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 Army’s now-defunct artificial-blood program. “He was one of the first people who said, ‘This isn’t just blood; that’s 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 products-as 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 TBI-and no drug therapy. Which is precisely why Spiess has chosen to focus on it.
“The FDA is in some ways pressured, because one, there’s 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, there’s a major international event going on, and we’re 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 Afghanistan-twice 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 victim’s memory, leave him blind, trigger epilepsy, or kill him outright. Many are calling it this war’s signature wound. So it’s 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 anemia–even spinal-cord injuries.”
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.
“It’s 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 doesn’t 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 person’s 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. “There’s not a lot of room for error,” Highsmith says, “even under normal circumstances.”
Once the spinal cord-or any organ-is injured, these incredibly
narrow vessels constrict even further, a reaction some researchers believe must be the body’s way of preventing blood loss. The defense mechanism’s 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 didn’t get Oxycyte. “It’s like a miracle drug,” he says. “Like pouring oxygen over the tissues.”
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. Northfield’s 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 we’re 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 it’s infused (air contains 21 percent oxygen). “That’s a logistical limitation,” Gould says, “and in general, it’s preferable not to breathe supplemental oxygen if it can be avoided.”
Most of today’s ambulances carry oxygen on board, as do military rescue helicopters, so the problem isn’t getting a tank of air to the patient. It’s 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 hasn’t 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 blood’s ability to clot; and some suffered short-term flu-like effects. Spiess has a quick response to concerns like these: “If you’ve been hit in the head or you’ve been shot or you’re having a stroke, you don’t sweat the flu-like symptoms.” All drugs have some measure of toxicity, Spiess says. It’s simply a case of the good outweighing the bad.
Although the sample size is far too small to be statistically definitive, it seems that VCURES’s 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-Lyn’s 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 country-perhaps as soon as next year.
Nicole Davis is a journalist based in Brooklyn.