Maybe they were calling it a night. Maybe they were on their way home. Some details are fuzzy. But this much is known. Two young college buddies were out late, drinking. The car they were riding in was speeding. It went off a Denver highway and overturned. Neither was wearing safety belts. The year was 1983.
Surgeon Brack G. Hattler remembers his phone ringing before dawn. He went to the hospital where the young men had been rushed. He tucked X-ray films into a light box, then carefully scanned the images. The legs of both men were badly crushed, but neither had lung or chest injuries. Not so much as a cracked rib. Hattler put away the X-rays. He was thinking they might do all right.
Instead, both men soon died, fighting for breath.
"They had a bright future ahead of them," says Hattler, a cardiothoracic surgeon, professor of surgery, and executive director of Pitt’s Artificial Lung Laboratory at the McGowan Institute for Regenerative Medicine. "We were doing everything we could, but still it wasn’t good enough."
What caused the deaths was no mystery, even then. Both men essentially drowned after their lungs filled with protein-rich plasma.
There are up to 150,000 cases of adult respiratory distress syndrome (ARDS) every year in the United States, according to the American Lung Association. ARDS is not a specific disease but, rather, a cascading series of changes deep in the lungs that ultimately leads to breathing failure. The twist is the primary injury does not always involve the lungs.
Today, the mortality rate from such cases ranges between 40 percent and 50 percent, a rate that is little changed since Hattler tried to save the two college students in Denver some 20 years ago.
Although many details of the Denver crash have faded, such deaths can leave doctors like Hattler with searing memories. These patients often die, despite heroic efforts by medical teams to provide air. The high mortality rate could be reduced if, somehow, the lungs could be temporarily relieved of their role in getting oxygen into the bloodstream. Hattler resolved to find a way. Within months of the student deaths, he had shifted his research from immunology to development of an artificial lung. The gadget would enrich the blood with oxygen, allowing the lungs to be bypassed.
Little could Hattler have imagined how his search for an artificial lung would also lead to the formation at Pitt of what is perhaps the first research committee of its kind in the world, a committee that may even serve as a model for other academic and medical centersand perhaps even the federal governmentin developing guidelines for what is expected to become a burgeoning area of research.
Hattlerwho performs many of the 50 or so lung transplant operations each year at UPMC Presbyterian Hospitalbegan research for an artificial lung in his garage in 1983. A machinist made parts for his early contraptions. The idea was to make a catheter small enough to be threaded through a vein in the leg and snaked into one of the heart’s big vessels. There, it would swap molecules of carbon dioxide for oxygen, doing the main work of the lungs. Animal experiments with calves followed: Improvements were made to the device. More experiments. More improvements.
Hattler came to Pittsburgh in 1989 to become a professor of surgery and direct the Artificial Lung Laboratory. He brought with him a patented device called an intravenous membrane oxygenator, which was an early version of the artificial lung that he envisioned. Design work continued at Pitt.
In 1995, William J. Federspiel, associate professor in Pitt’s Departments of Chemical Engineering, Surgery, and Bioengineering, was recruited by Hattler to serve as director of the fledgling artificial lung lab. Hattler became the lab’s executive director as he and Federspiel formed a company to make and market his new product, the Hattler Respiratory Support Catheter. Alung Technologies opened for business last year with the goal of launching the world’s first commercial artificial lung in 2006. More important, the device will be safer and cost less than mechanical ventilation, the primary treatment today for people with acute lung problems like those that ultimately claimed the lives of the two Denver students.
Two full-time staff professionals and a half-dozen graduate students staff the 1,500-square-foot artificial lung laboratory at the McGowan Institute. The institute was founded in July 2001 as a joint project of the School of Medicine and UPMC. Tissue engineering, cellular therapies, biosurgery, and biohybrid and artificial organ devices are among the projects scientists have undertaken. In its first two years of operation, McGowan has grown to include more than 170 faculty and 500 students and staff. The institute also has more than 70,000 square feet of new lab and office space on Pittsburgh’s South Side, minutes from Pitt’s Oakland campus.
Hattler’s project launched the artificial lung laboratory 10 years ago. Now, many other projects are under way there, with scientists and students working together on the next generation of artificial lungs. These devices may serve as a bridge for people awaiting lung transplantation, filling a critical need. Some 4,000 people are currently awaiting lung transplantation, according to the United Network for Organ Sharing, a Richmond, Va.-based scientific and educational organization established by the U.S. Congress in 1984.
Other work at the lab centers on making artificial lungs more biocompatible and efficient. Creating smaller designs and boosting gas exchange capacity are additional goals. The work may one day lead to artificial lungs that can be worn outside of or implanted in the body.
The latest incarnation of Hattler’s artificial lung is roughly 40 percent as efficient as healthy lungs at rest. Still, the device works two to three times better than Hattler’s first design.
With human experiments of this device more than a year away, pressing questions remain. "No one knows exactly how much carbon dioxide has to be removed from the blood to support life," Federspiel says, citing one unknown. There are other questions, too.
The artificial lung, which is really a catheter, must be slipped into a vessel near the heart. This vessel, which is called the vena cava, carries blood to the heart, where it is pumped into the lungs for gas exchange. In the lungs, blood unloads carbon dioxide that has been collected from the furthermost reaches of the body, then picks up oxygen. Despite the testing so far, it’s still not known how well the device will work in people, Federspiel says. "There’s no way to simulate an experiment for that," he says. "A calf’s vena cava is not a human vena cava."
Hattler puzzled over methods for predicting how well the catheter would serve as an artificial lung. Then he had an idea.
Death had been a fairly straightforward affair for centuries. A person stopped breathing and burial arrangements began. Things began to change by the 1740s after several people, first thought to be dead, were revived. Such reports spawned formation of an early rescue squad in 1774the Society for the Recovery of Persons Apparently Drowned. Within months of its founding, a society member saved a 3-year-old child who had been pronounced dead after a fall onto flagstones from an upper-story window. Cases like these showed that with prompt treatment, some people who were believed dead could be brought back to life. The line between life and death had to be redrawn.
By the early 1960s, medical advances not only allowed the resuscitation of people who would have been declared dead in an earlier age; the advances enabled doctors to keep a patient’s body alive long after the brain had died. A new definition of death was needed. There had always been clinical death, which is what happens when the heart stops beating. Starting in 1968, there was brain death, which was defined by an ad hoc committee at Harvard Medical School. The committee determined that death also meant irreversible coma without brainstem function and inability to breathe without ventilatory support, regardless of whether the heart was still beating. Brain death has come to mean the end of life just as the absence of breathing and cardiac arrest had each defined death for centuries. The brain-death definition is generally accepted around the world.
Hattler first approached a few people at the Pittsburgh-based Center for Organ Recovery and Education (CORE) to broach the idea of testing his artificial lung in the brain-dead. He then discussed his thoughts with Federspiel and several other colleagues. Soon after, he contacted the University’s Institutional Review Board (IRB), a group of doctors and scientists who review requests for research involving humans. Dennis Swanson, professor and assistant dean, School of Pharmacy, and the IRB vice chair and director of the IRB office, told Hattler that, based on federal regulations governing IRB activities, the board’s authority technically extended only to research involving living peoplenot the dead. Hattler was in uncharted medical territory.
In March 2000, Federspiel turned to Michael A. DeVita, an internist and critical care physician, who chairs UPMC’s Hospital Ethics Committee. In an e-mail message, Federspiel outlined the possibility of using brain dead people to try out the artificial lung. DeVita, an assistant professor in the departments of Anesthesiology/Critical Care Medicine and Internal Medicine, immediately recognized how the use of brain-dead test subjects might yield vital information before trials in living patients begin.
"It’s an excellent opportunity to make some really huge improvements in the quality of care you can give people," says DeVita, who is also past chair of the Society of Critical Care Medicine Ethics Committee. DeVita saw something else, too. "I don’t doubt this kind of research is going to explode in the future." His UPMC committee approved the idea and then began developing guiding principles for this new research.
This process ultimately led to the birth of a new entity, the Committee for Oversight of Research Involving the Dead (CORID). The committee is specifically designed to evaluate and monitor research that uses for subjects people who are brain dead.
At some institutions, experiments on patients declared brain dead might take place with few people knowing about it, according to Alan Meisel, professor of law and bioethics at the University and director of Pitt’s Center for Bioethics and Health Law and an international authority on end-of-life issues.
That will not be the case at Pitt. Doctors and others say the establishment of CORID is a first. "It has become recognized nationally as a novel idea," says committee chair Clifford Schold, who is associate vice chancellor for clinical research in Pitt’s schools of the health sciences. "There are no federal regulations covering this."
Family consent and clear communication of any proposed experiments are key to board reviews, says committee member Sister Mary Kay Hammond, who is a staff chaplain at several UPMC hospitals. "Families do want to help with research as long as everything is explained to them."
Experimentation involving brain-dead people also makes sense to Brian Broznick, executive director of CORE, which coordinates organ recovery and transplantation among 160 hospitals in the tri-state region. Fully 90 percent of people who offer to donate organs are unsuitable for a variety of reasons, Broznick says. "There are a number of families who want to help someone else. This gives them an opportunity to help."
Medical progress has long been dependent upon patients and families volunteering for clinical trials, says Arthur S. Levine, senior vice chancellor for the Health Sciences and dean of the School of Medicine. Organ transplantation and the dramatic reduction in childhood leukemia deaths in recent decades are just two examples of how such experiments have benefited thousands of people worldwide.
Bioethicist Arthur L. Caplan praises Pitt’s pioneering efforts in establishing guidelines for research involving the brain dead. "If the choice is between testing a new drug on a brain-dead person or my child, the dead person suddenly sounds like a whole lot better idea," says Caplan, who is director of the Center for Bioethics at the University of Pennsylvania in Philadelphia.
Since CORID was formed a year ago, the panel has approved two experiments involving the artificial lung and brain-dead patients. Up to 10 more tests on people declared brain dead are anticipated, Hattler says. The tests are expected to provide key information before testing on living people gets under way in a year or so.
Further testing could mean still other improvements to the device, which ultimately may get it to market sooner than otherwise possible. And treating people with adult respiratory distress syndrome will not be the only use of the device. Nearly 16 million Americans suffer some kind of lung disease, including two million people who have emphysema, according to the American Lung Association.
For many of these people, a case of flu or pneumonia can quickly become fatal because the lungs are already weakened by disease. Hattler’s artificial lung could temporarily provide oxygen needed by the body while allowing the lungs to heal. The latest version of the artificial lung is expected to fill in for a person’s lungs for up to three weekslong enough to have saved those college students who died in Denver 20 years ago.
Kris Mamula is a senior editor at Pitt Magazine. (Sadly, Brian Broznick died not long after being interviewed for this story.)
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