From the issue dated November 29, 2002
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Battling for Hearts and MindsResearchers seek to understand and prevent memory loss in bypass-surgery patientsBy LILA GUTERMAN Your memory or your life? That's the unnerving question that many heart-surgery patients face. Some 600,000 Americans will undergo heart-bypass operations this year, and research suggests that half will suffer memory loss or other cognitive difficulties in the months that follow. Although the declines tend to be mild and some patients recover, a recent study found that more than two in five will suffer deficits in brainpower five years after surgery. Doctors have known about what they call postoperative cognitive dysfunction for decades, but only recently have they begun to pin down the problem's magnitude and causes. Now they are experimenting with ways to prevent it, such as cooling the brain during surgery and devising safer surgical techniques. James E. Cottrell is optimistic about the progress toward understanding and avoiding brain damage from surgery. Dr. Cottrell, who is president of the American Society of Anesthesiologists and a professor of anesthesiology at the State University of New York Health Science Center at Brooklyn, says, "If we keep on this road, we can really prevent this from happening." Cardiologists and surgeons often hear that a patient was "just not the same" after surgery. Although only a tiny fraction of patients suffer major strokes during heart operations, there are widely varying estimates of the percentage of people with subtle brain problems, such as difficulty recalling specific words, trouble planning several steps in advance, and loss of some hand-eye coordination. That is because of differences among the mental tests used, the surgical methods, and the patients themselves. Doctors think that about 40 to 60 percent of patients over the age of 60 experience cognitive problems after heart surgery. Most doctors assumed the declines were temporary until Mark F. Newman and his colleagues at Duke University discovered otherwise. In a study published last year in The New England Journal of Medicine, Dr. Newman, the anesthesiology department's chairman, found that among 261 bypass patients, more than half performed at least 20 percent worse on cognitive tests when they left the hospital. Six months later, many had improved and only 24 percent showed that level of cognitive trouble. But the fraction with a 20-percent decline in brainpower jumped back up, to 42 percent, after five years. The same people who had experienced early problems tended to show later declines as well. Dr. Newman received 4,000 e-mail messages after the paper appeared, many from patients but some from other researchers who faulted the study for using no control group for comparison. "That was a criticism I agree with," says Dr. Newman. The patients with long-term decline might have suffered memory loss even without having had surgery. Hilary P. Grocott, an associate professor of anesthesiology who works with Dr. Newman at Duke, points out that it would be hard to study the perfect control group: people with heart disease who did not undergo surgery. "Those patients would be dead at five years," he says. But the Duke group is now following people who had types of surgery considered less likely to cause cognitive problems. Among those patients are some with heart disease who underwent a procedure without general anesthesia called balloon angioplasty, in which an inflating balloon reams out a clogged blood vessel and a stent is inserted to keep it open. Guy M. McKhann, a professor of neurology and neuroscience at the Johns Hopkins University, is conducting a similar study, which also follows patients with no heart disease. In work that is not yet published, he found that, compared with healthy volunteers, the patients with heart disease tended to score lower on cognitive tests even before surgery. "It's likely that the blood vessels in their brain aren't normal," he says. Underlying disease may predispose those patients to brain injury during surgery, making their later cognitive performance even worse. After one year, Dr. McKhann's patients who had surgery were more likely than other patients to complain about their memories, though they did not fare significantly worse on tests. He wonders if those people are the ones who will go on to have measurable memory loss in subsequent years of the study. "Our bet is that they are," he says. 'Pump Head' Now that doctors have started to recognize the magnitude of the mental decline after surgery, they are racing to find the source of the problem. A consensus has emerged that the brain problems stem at least in part from tiny particles that travel to the brain during surgery and cause ministrokes. The particles, made up of fat, blood clots, or air bubbles, are thought to block blood vessels and prevent small regions of the brain from getting oxygen and nutrients. Some of those particles may get knocked loose from artery-clogging plaque when doctors clamp off the aorta during surgery. According to David A. Stump, an associate professor of anesthesiology and cardiothoracic surgery at Wake Forest University's Health Science Center, the particles also come out of bones that are severed to give access to organs like the heart. "When you cut the sternum, the bone marrow leaks out," he says. "A lot of it is the consistency of Wesson oil." The particles also develop in the heart-lung machine, which oxygenates and circulates blood to the body while the heart is stopped for surgery. In the heart-lung machine, blood clots form and air bubbles appear. Some operating rooms have filters that remove many of the larger particles. Still, doctors largely continue to blame the pump for cognitive dysfunction. "People call it 'pump head,'" says Dr. Newman. But trials comparing off-pump surgery to traditional bypass operations have produced mixed results. Some early studies showed that patients who underwent off-pump procedures, done on the beating heart, had fewer memory problems after surgery. But a large Dutch trial on 281 patients, published in March in The Journal of the American Medical Association, found no significant difference 3 or 12 months after surgery. "It's not the pump," says Mr. Stump. "It's the trash you send to the brain." The key, he says, is keeping the garbage from getting there. One way to do that, he has found, is to cool the brain, a step that slows its metabolism and reduces the blood flow it needs. While using heart-lung machines, Wake Forest surgeons also clamp the aorta fewer times, limiting the debris discharged there. They also reduce how much blood comes in contact with air, decreasing the number of air bubbles. As a result of such changes, Mr. Stump says, only one in six bypass patients at Wake Forest experiences long-term memory problems. The Duke researchers have also looked at the effects of temperature change. When rewarming cooled patients, surgical teams often overshoot normal body temperature, Dr. Grocott says. In April, the Duke group published a study in Anesthesia & Analgesia showing that patients who were rewarmed more slowly were less likely to experience memory loss six weeks later. Overheating the brain after surgery could worsen subtle injuries, Dr. Grocott says. Protecting the Brain Even when surgeons take the precautionary steps of cooling their patients or operating without pumps, scads of particles find their way to the brain during surgery. Because stanching the flow altogether seems impossible, researchers are coming up with strategies to mitigate injury once the particles arrive in the brain's blood vessels. The body responds to major surgery with inflammation, unleashing white blood cells that may kill injured brain cells rather than letting them heal. Scientists think that some drugs given before surgery may quiet the subsequent inflammatory response or protect brain cells from it. Dr. Cottrell, of SUNY, has tested in rats a drug called erythropoietin, which causes the brain to produce proteins that aid cell recovery, as well as one called lidocaine and a magnesium compound, each of which indirectly reduces cells' oxygen requirement. Those drugs are among several being tested in humans. Mr. Stump is studying other drugs that influence brain cells less directly. He says that the particles in the blood may be wreaking havoc not by blocking blood vessels but by making them leak. He has found that after a fat particle passes through a blood vessel in the brain, "suddenly all sorts of material can leak through and cause swelling." He is testing in dogs a drug called aprotinin to protect the blood vessels, rather than the surrounding brain cells. Anesthesia at Fault? Other scientists are examining whether part of the brain damage comes from the anesthesia itself. Not surprisingly, that has been an unpopular idea among anesthesiologists. "Anesthesiologists believe that if you get anesthesia, when the anesthetic is over and you're awake, your brain is back to normal," says Gregory Crosby, an associate professor of anesthesia at Harvard Medical School. Instead, they have said that the heart operation was to blame. But an international team of researchers raised doubt in 1998, when it published a study finding that elderly patients having noncardiac surgery also experienced memory loss. Perhaps, as with bypass patients, particles dislodged during surgery went to their brains, but many of the usual suspects, including the heart-lung machine and already-clogged arteries, were absent. Dr. Crosby and his colleague Deborah J. Culley wanted to distinguish between the effects of surgery and of anesthesia. In work that has been submitted for publication, they anesthetized old rats without doing surgery and then tested the animals' ability to learn a maze. The researchers found learning impairments in the rats two to four weeks after anesthesia. "That's one to two years in people terms," Dr. Crosby says. "The brain is not like a light bulb," he continues. "You don't just turn it on and turn it off. When it comes back on, it might be a little dimmer, for longer than we thought." Even though the anesthetic is no longer in the body, the brain still feels its effects, perhaps because of a change in brain chemistry. "We are not saying that anesthesia is bad for you," he says. "No one would choose to have surgery without anesthesia." In fact, he says, it is even possible that anesthesia might somehow lessen the problems caused by surgery. Because doctors mainly see cognitive problems after surgery in people over 60, Dr. Crosby has not tested young rats. He suspects anesthesia would cause less impairment in younger people. "The old brain is very, very different than the young or middle-aged brain," he says. Brains shrink as they age, and their chemistry changes, making them more vulnerable to injury. As for older patients, researchers agree that the risk of cognitive difficulties should not dissuade patients from undergoing lifesaving operations. "The one thing to remember is that these are mild changes," says Terri G. Monk, a professor of anesthesiology at the University of Florida. Some patients do not even notice them, while others might only forget telephone numbers or have difficulty solving crossword puzzles. Fine-Tuning for Safety Dr. Newman notes that memory loss afflicts only a fraction of patients, in either the short or long term. "I've had people call me and say, 'I've had my surgery and I'm doing much better than I've ever done. I feel brighter and more alert,'" he says. "Our goal was to have the rest of the patients be able to say that as well." Dr. Monk is often asked why doctors did not focus earlier on the problem of postoperative memory loss. She responds that the mental declines are minor compared with the difficulties doctors faced earlier. "We were so busy trying to keep people alive," she says. "We can do that quite successfully now." Scientists and doctors can now work to refine the techniques to eliminate more-subtle problems. What's more, improvements in surgical and anesthetic methods have meant that elderly patients, who used to be considered too vulnerable to undergo surgery, are now being operated on routinely, she says. Those older patients are inherently more likely to experience cognitive declines. The aim of the research, says Dr. Newman, is "to make a safe operation even safer." Then, researchers hope, patients will be able to choose their memories and their lives. http://chronicle.com Section: Research & Publishing Volume 49, Issue 14, Page A12
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Copyright © 2002 by The Chronicle of Higher Education