Ways to avoid hazards of heart bypass under study

Aug 28 2005

The heart-lung bypass machine that stills the heart while surgeons bypass an adult’s clogged arteries or repair a baby’s malformed heart can also trigger a potentially deadly inflammatory response.

That unfortunate fact has Medical College of Georgia surgeons participating in an international study of a drug that may block the most deadly of these responses in adults who have coronary bypass surgery.

It also has them trying to better understand the process in children whose complex heart defects often mean they spend hours or even days on heart-lung bypass.

“We have to remember that blood is a very complex fluid with many components,” says Dr. Kevin P. Landolfo, chief of the MCG Section of Cardiothoracic Surgery. Like the heart, three to six liters of blood run through the heart-lung bypass machine per minute, which means total blood volume goes through the machine many times in the hours it takes to perform bypass surgery. “It’s a massive physiologic insult like a major trauma, so our body comes alive with an inflammatory response to circulating through this unit,” Dr. Landolfo says.

The response helps prevent infection, but it can cause blood clots that lead to serious complications – including lung or kidney injury, a heart attack or stroke – in 7 percent to 10 percent of patients.

MCG is part of a study to determine whether giving the complement blocker pexelizumab intravenously before, during and after bypass surgery blocks the worst aspect of the inflammatory response. “The immune system is still revved up but we block the most dangerous component of it,” says Dr. Landolfo.

Surgeons have long recognized the ill effects of bypass. They have changed the way they do surgery, even doing cases without bypass when possible, and the machine itself has been improved, says Dr. Landolfo. “We are pretty good at having patients survive, but it’s all the morbidity related to heart surgery. Much of what remains is related to the heart-lung machine.”

The study of 5,000 heart bypass patients in about 40 states and three foreign countries is looking at this drug in at-risk patients, including those who have had a previous stroke or heart attack or have diabetes. Women also at risk for serious complications, possibly because their smaller size causes their blood to pass through the machine even more times, Dr. Landolfo says, noting treatment protocols already take this risk into consideration.

He’s optimistic all bypass patients may one day benefit from some form of short-term suppression of the protective immune response, but for purposes of the study – sponsored by Alexion Pharmaceuticals Inc. and P&G Pharmaceuticals – it’s easier to show results in high-risk patients.

His colleague, Pediatric Cardiothoracic Surgeon James D. St. Louis, is trying to understand this potentially lethal inflammatory response in children. “Their response can be profoundly different and profoundly more intense than adults. Children die from it,” Dr. St. Louis says. “We have at least one or two children a year where the operation goes fine then the children will have this spiraling set of circumstances where there is nothing you can do. It’s an immune response,” he says of systemic inflammatory response syndrome following bypass.

“Remember, the vast majority of children do fine,” says Dr. St. Louis. But he thinks some children, particularly those with low oxygen levels before surgery, have trouble activating a natural mechanism that could correct some cell damage caused by bypass.

As blood moves through the machine where carbon dioxide is removed and oxygen is added, oxygen-carrying red blood cells literally get beat up. “It’s a lot better than it was 15 or 20 years ago but it still cause hemolysis,” says Dr. St. Louis. Oxygen-carrying, iron-rich hemoglobin is supposed to be carried by red blood cells. But it can escape from bypass-battered cells, generating oxygen-free radicals that destroy tissue. Macrophages, scavenger-like cells that roam the body, have a surface receptor called CD 163 which binds the protein haptoglobin. Haptoglobin in turn binds free-floating hemoglobin so the macrophages can eliminate it. “One of the theories we have is that in some children, CD 163 may be deficient or not up-regulated as much as it should be,” says Dr. St. Louis.

To better understand the action of CD 163 in these children, Dr. St. Louis is measuring levels in newborns before, during and after surgery and looking at the expression of macrophages in heart tissue.

He’s also looking at the complement system activated by bypass which in children can cause leaking of endothelial cells that line blood vessels. “One of the biggest problems after surgery is the kids swell,” Dr. St. Louis says, a result of this leaking than can pull the blood vessel wall lining apart. “We are trying to figure out why at this point,” he says, noting that children already receive steroids beforehand to up-regulate CD 163 and suppress the immune response.

He believes the ‘why’ may again be an issue of mal-regulation. One of his clinical studies is looking at expression of factors that regulate immunity, such as NFkappaBeta, in hypoxic and non-hypoxic children. He’s also looking at the contributions of NFkappaBeta to cell leakiness that occurs in some children. “We want to figure out what causes leakiness so we can stop it,” says Dr. St. Louis, who says it’s likely a signaling process that goes back to the oxygen-free radicals released by battered red blood cells.

An animal model he developed is enabling even more detailed studies of both problems.