Air bubble: An intravenous infusion of oxygen-filled microparticles (the yellow sphere in this composite image) could carry the life-sustaining gas to red blood cells in patients with sudden loss of lung function.
Because of pneumonia, the patient’s lungs were filling with blood. There was only one option to save the little girl, and so the team including cardiologist John Kheir—who was in training at the time, in 2006—raced to get her hooked up to a heart–lung machine, an external device that oxygenates and pumps blood around the body. But connecting a patient to the machine takes time, and the girl’s blood oxygen levels were dropping fast. She suffered severe brain damage and died before the team could even connect her to the machine. “I was pretty frustrated that we were unable to support her oxygen delivery, even though she was already in intensive care,” Kheir tells PM. But that frustration was the germ of a potential breakthrough: “I thought that maybe we could get rid of the need for the lungs to provide oxygen, by injecting it into the bloodstream.”
Beginning in World War I, doctors attempted to inject oxygen gas straight into patients’ bloodstreams, but to no avail. Instead of raising the patients’ blood oxygen levels, the gas gathered in air bubbles that fatally blocked blood flow. But this week, in a paper published in Science Translational Medicine, Kheir and his colleagues at the Boston Children’s Hospital say they have found a way to package oxygen inside of microscopic shells. Once injected, the flexible coatings can pass the oxygen directly to the red blood cells before the gas has a chance to form bubbles. The oxygen microparticles may one day allow doctors to safely inject oxygen directly into patients who can’t breathe through their nose or mouth.
The oxygen microparticles haven’t been tested on humans yet, so it would be years before they entered the ER. But “the notion that one could have an intravenous agent to deliver oxygen to the bloodstream, without gas bubbles, is pretty exciting work,” says David Wessel, a critical care specialist at Children’s National Medical Center in Washington, D.C. When a patient suffers a blocked airway or damaged lungs, “the measures to try to establish an airway can be pretty extreme,” Wessel says. Doctors may have to cut a small hole through the neck and windpipe (in a procedure called a tracheostomy), or put the patient into a heart–lung machine, which can be labor intensive and high risk. Without oxygen, the body may go into cardiac arrest or suffer brain damage.
A Few Minutes More
The researchers started by creating tiny (4-micrometer-wide) air bubbles by filling a chamber with oxygen, a kind of molecule called phospholipids, and a fluid similar to blood plasma. They fired sound waves at the chamber so that the gas and fluids would mix. During that process, the fatty phospholipids encircled the oxygen gas—similarly to the bubbles that form when you shake up a bottle of oil and water mixture—and the phospholipid shells hold the oxygen in suspension. When mixed with blood, the oily bubbles readily give up their oxygen to the hungry red blood cells. “The chemistry basically does all the work,” Kheir says. In a preliminary experiment, the researchers anesthetized rabbits and gave them a paralyzing medication so that they could not breathe on their own. They cut off each rabbit’s air supply for 15 minutes. Seven rabbits received injections of the oxygen microparticles, which kept their blood oxygen levels above the danger zone. Rabbits in this group fared well. But the control group didn’t receive oxygen of any kind; all six suffered cardiac arrest and organ failure.
Notably, though, one rabbit injected with the oxygen microparticles suffered cardiac arrest, apparently because of a buildup of carbon dioxide. That’s the concern with these particles, according to Warren Zapol, an anesthesiologist at Massachusetts General Hospital who doubts their practicality: If an animal is unable to exhale CO2, the gas fuses with water in the blood to form carbonic acid, which can lead to organ failure. “Obviously [this treatment] doesn’t remove carbon dioxide so it’s only doing half the job,” he says. “You can live with your carbon dioxide going up, but you won’t be a happy person. Can you buy a few minutes with this? Maybe.” Stephen Trzeciak, an emergency medicine and critical care specialist at Cooper University Hospital in New Jersey, disagrees. “I don’t see carbon dioxide as even being an issue. Having a high carbon dioxide level isn’t what kills people. It’s the lack of oxygen.” It’s true that the oxygen microparticles would not sustain a person indefinitely. “I think it’s conceivable that [the treatment] could keep someone alive for 20 or 30 minutes,” Kheir says. But in the emergency room, Trzeciak says, even a few extra minutes can be a precious resource. “You could infuse the oxygen intravenously, to get enough oxygen into the blood while you get a definitive fix on whatever is wrong.” He says that the treatment could keep oxygen levels stable while doctors perform a tracheostomy or hook the patient up to a heart-lung machine—perhaps providing the stopgap solution that Kheir needed back in 2006.
Because humans are much larger than rabbits, keeping a person’s blood oxygen levels up during an emergency would require injecting much larger volumes of the oxygen microparticles continuously. Kheir estimates that to keep an adult alive for ten minutes, doctors would need to inject 2 liters of oxygen microparticles into the patient’s body. Imagine trying to empty a 2-liter soda bottle into your blood stream in just a few minutes. Fortunately, he says, your hemoglobin picks up oxygen quickly and the empty phospholipid shell collapses, so the actual volume added to the bloodstream is closer to 600 or 700 milliliters. Kheir would like to decrease that volume even more by increasing the concentration of microparticles, but the team has its work cut out. Although Kheir and colleagues managed to create a substance that contained 90 percent oxygen microparticles and only 10 percent fluid, the substance had the consistency of shaving cream and couldn’t be injected effectively. The mixture that they tested in rabbits was closer to 65 percent oxygen. The team also must determine any long-term risks of the treatment, and figure out how the body breaks down the phospholipids shell once it releases its oxygen, before a drug like this makes it to the hospital. “There’s a lot of obstacles that would have to be dealt with,” Wessel says, “but this represents a very novel idea with potentially enormous benefits.”
RABBITS KEPT ALIVE
Infusions of microparticles could prevent heart attacks and brain damage.
by Duncan Graham-Rowe / 27 June 2012
Rabbits with blocked windpipes have been kept alive for up to 15 minutes without a single breath, after researchers injected oxygen-filled microparticles into the animals’ blood. Oxygenating the blood by bypassing the lungs in this way could save the lives of people with impaired breathing or obstructed airways, says John Kheir, a cardiologist at the Children’s Hospital Boston in Massachusetts, who led the team. The results are published today in Science Translational Medicine1. The technique has the potential to prevent cardiac arrest and brain injury induced by oxygen deprivation, and to avoid cerebral palsy resulting from a compromised fetal blood supply. In the past, doctors have tried to treat low levels of oxygen in the blood, or hypoxaemia, and related conditions such as cyanosis, by injecting free oxygen gas directly into the bloodstream. They had varying degrees of success, says Kheir.
Full of air
In the late nineteenth century, for example, US doctor John Harvey Kellogg experimented with oxygen enemas — an idea that has been revived in recent decades in the form of bowel infusers2, says Mervyn Singer, an intensive-care specialist at University College London. But these methods can be dangerous, because the free oxygen gas can accumulate into larger bubbles and form potentially lethal blockages called pulmonary embolisms. Injecting oxygen in liquid form would avoid this, but the procedure would have to be done at dangerously low temperatures. The microcapsules used by Kheir and his team get the best of both worlds: they consist of single-layer spherical shells of biological molecules called lipids, each surrounding a small bubble of oxygen gas. The gaseous oxygen is thus encapsulated and suspended in a liquid emulsion, so can’t form larger bubbles. The particles are injected directly into the bloodstream, where they mingle with circulating red blood cells. The oxygen diffuses into the cells within seconds of contact, says Kheir. “By the time the microparticles get to the lungs, the vast majority of the oxygen has been transferred to the red blood cells,” he says. This distinguishes these microcapsules from the various forms of artificial blood currently in use, which can carry oxygen around the body, but must still receive it from the lungs.
Safe and sound
The lipid foam is safe, says Kheir. “As the oxygen leaves them, the shells buckle and fold, with the lipids breaking off,” he says. The body then reabsorbs the lipids. Injected rabbits survived for up to 15 minutes without breathing, and had normal blood pressure and heart rate. They showed no indication of heart, lung or liver damage caused by oxygen deprivation, or of pulmonary embolisms. The microcapsules are easy and cheap to make, says Kheir. They effectively self-assemble when the lipid components are exposed to intense sound waves in an oxygen environment — a process known as sonication.
It is a very sophisticated approach, says Singer. Heart–lung machines can also oxygenate the blood, he notes, as can extracorporeal membrane oxygenation, in which blood is pumped out of the body, oxygenated and then pumped back in. However, these techniques are more suited to surgery or longer-term life support, and would not be much use in emergency situations such as when someone’s windpipe became blocked, says Singer. Kheir agrees, saying that one of the great advantages of the microparticle approach is the speed at which it works. He thinks that it might be possible to modify the technique to keep subjects alive for as much as 30 minutes, but doubts that it could be pushed much further. Because the microparticles do not recirculate, it would be necessary to continuously infuse fresh ones into the blood, and there are limits to how much extra fluid can be pumped into the bloodstream. “It’s not going to replace the lungs, it just replaces their function for a limited period of time,” says Kheir.
1. Kheir, J. N. et al. Sci. Transl. Med. 4, 140ra88 (2012)
2. Gross, B. D. et al. Artif. Organs 24, 864–869 (2000)
Researchers have developed a way to deliver oxygen to the body’s organs safely—via gas-filled microparticles—even when the patient’s lungs have stopped working. Doctors could one day use the method to quickly reverse oxygen deprivation in patients with acute loss of lung function while longer-term fixes such as heart-lung bypass support are put in place. Even short periods of oxygen deprivation put the vital organs of the body at risk. Typically, doctors feed oxygen-deprived patients the gas through ventilators such as tubes in the mouth or nose, but the treatment depends on functioning lungs. In situations where the airway is blocked or the lungs do not work, few options exist. In such cases, injecting pure oxygen into the body is not an option because it can form bubbles in blood vessels and block blood flow. Some hospitals have machines that can oxygenate a patient’s blood outside of the body, but the surgical procedure to hook up such a bypass machine is complicated and can take too long in an emergency, says study author John Kheir. As a first-year fellow at Boston Children’s Hospital a few years ago, Kheir treated a nine-month-old girl whose lungs had been damaged by pneumonia and were filled with blood. In the 20 or so minutes it took for Kheir and his colleagues to put her on the heart-lung bypass machine, she suffered severe brain injury from low oxygen levels and died. The experience led Kheir to work toward developing a fast-acting, intravenous treatment that could help patients like her with acute, severe lung injury. “The only way to save someone like that would be to inject oxygen directly into the vein,” he says.
Blood substitutes that carry oxygen are available for transfusion, but are known to cause dangerous side effects and furthermore typically rely on functioning lungs. “There really is a need for something that you can pull off the shelf, and give to people to pull them through these critical periods,” says Ann Weinacker, a lung and critical care doctor at the Stanford Chest Clinic. Kheir’s oxygen-filled microspheres, reported today in Science Translational Medicine, are around three micrometers in diameter and are diluted in a solution commonly used in transfusions so that the particles can flow through even small capillaries in the body. In test tubes, the researchers found the oxygen transferred from the microspheres to hemoglobin, the protein in red blood cells that carries oxygen, within four seconds. They then tested the microspheres in anesthetized rabbits with blocked windpipes. Although the rabbits were asphyxiated, their bodies were oxygenated and did not show signs of major injury to organs. More research is necessary to determine how long the therapy can work and for how many patients it could be useful. “Situations where you have a short-term need [for oxygen] and everything else is working are not that common,” says Gail Weinmann, a lung disease expert with the National Heart Lung and Blood Institute. But when those situations arise, a quick infusion of oxygen could be life-saving, she says. “As a bridge, even 15 minutes could make a difference in some situations.”
Kheir says the intravenous oxygen delivery could help not only in the critical moments when heart-lung bypass machines are being set up, but also when patients are being put in intensive care on ventilators. Unstable patients with low lung function are also at risk of severely low oxygen levels, he says. “[The goal] is not to make ventilators obsolete, but to make patients healthier,” says Kheir, and that more lab animal work is needed to explore the clinical utility of the microsphere technology, which he and some of the study coauthors are patenting. “We are testing the ability of these particles to deliver oxygen in other clinical circumstances, such as cardiac arrest and severe bleeding,” he says. The team is also working on making the microspheres more stable, with the ultimate goal of creating an off-the-shelf solution that could be ready for quick use in emergency situations.
email : john.kheir [at] childrens.harvard [dot] edu
We have developed an injectable foam suspension containing self-assembling, lipid-based microparticles encapsulating a core of pure oxygen gas for intravenous injection. Prototype suspensions were manufactured to contain between 50 and 90 ml of oxygen gas per deciliter of suspension. Particle size was polydisperse, with a mean particle diameter between 2 and 4 μm. When mixed with human blood ex vivo, oxygen transfer from 70 volume % microparticles was complete within 4 s. When the microparticles were infused by intravenous injection into hypoxemic rabbits, arterial saturations increased within seconds to near-normal levels; this was followed by a decrease in oxygen tensions after stopping the infusions. The particles were also infused into rabbits undergoing 15 min of complete tracheal occlusion. Oxygen microparticles significantly decreased the degree of hypoxemia in these rabbits, and the incidence of cardiac arrest and organ injury was reduced compared to controls. The ability to administer oxygen and other gases directly to the bloodstream may represent a technique for short-term rescue of profoundly hypoxemic patients, to selectively augment oxygen delivery to at-risk organs, or for novel diagnostic techniques. Furthermore, the ability to titrate gas infusions rapidly may minimize oxygen-related toxicity.