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en to 20 years ago, surgeons repairing broken hearts considered the surgery a success if the patient managed to survive the risky operation.

Today, only 2 percent to 3 percent of patients die after a major operation, but up to 10 percent to 20 percent may suffer from major complications and remain hospitalized for weeks with some degree of organ dysfunction or infection. "The ICU is filled up with patients having complications from surgery, so increasingly, this is recognized as a serious problem," says Dr. Elliott Bennett-Guerrero, the Florence Irving Assistant Professor of Anesthesiology and chief of cardiac anesthesiology.

Many of these heart patients develop trouble in the lung, the kidney, or other organs not directly involved in the operation. Dr. Bennett-Guerrero says an exaggerated systemic inflammatory response appears to be responsible for many of these complications.

Systemic inflammation behaves similarly to a local inflammation, but on a larger scale. If a finger, for example, has an infected paper cut, inflammation is the body's way of attracting white blood cells to go to the infected area, release antibodies, and spur the immune system to kill the invaders. In the process, the area around the cut becomes red and puffy.

But with systemic inflammation, "the white blood cells in your bloodstream are acting everywhere," Dr. Bennett-Guerrero says. "You're turning your whole body into something that looks like that finger." Some people only have minor manifestations of the widespread inflammation, but patients with severe manifestations suffer from life-threatening failure of multiple organs and septic shock.

Five years ago, Dr. Bennett-Guerrero reported in the Journal of the American Medical Association (Feb. 26, 1997) that heart patients with higher complications had lower levels before surgery of a certain antibody in the immune system that seems to neutralize endotoxin. In a more recent study, published in the June 2001 issue of Anesthesiology, Dr. Bennett-Guerrero found that a low level of this same antibody to endotoxin increases the risk of complications in patients having other types of surgery.

Endotoxin (also called lipopolysaccharide or LPS) is a necessary component of the outer wall of all gram-negative bacteria that normally live in the gut. The 25 billion nanograms of LPS in each person provoke little inflammation in the gut. In healthy individuals, the endotoxin from the normal death of bacteria gets released as waste. But during major surgery, ischemia, or lack of oxygen, in the gut causes endotoxin from decomposing bacteria to leak into the bloodstream, spurring the immune system to become activated.

In the JAMA study, Dr. Bennett-Guerrero found that patients who underwent cardiac surgeries and had a lower antibody level to endotoxin had a higher rate of complications. He measured the immune level by assaying for EndoCAb, an antibody that binds to endotoxin and directs its neutralization. He found that 23 percent of heart patients with a low level of EndoCAb had complications, while 4 percent of patients with high EndoCAb levels had complications.

Similar results were found in the Anesthesiology study of patients having a variety of operations, including hip repairs and hysterectomies. Patients with low levels of EndoCAb before surgery had twice as many complications as patients with high levels of the antibody.

Although Dr. Bennett-Guerrero's research points to endotoxin exposure during surgery as an important cause of complications, he says many clinicians still question its role based on a misunderstanding of the theory. Frequently, people confuse endotoxemia (endotoxin in the blood) with bacterial infection and expect to see the live organisms circulating in the patient's bloodstream and infecting the inflamed organs. However, he says, endotoxemia does not require the presence of live bacterial cells in the bloodstream.

Endotoxin is just one cause of systemic inflammation, though, and Dr. Bennett-Guerrero also is studying what he believes is the other major one: the release of oxygen free radicals during surgery. In this mechanism, ischemia/reperfusion—a lack of oxygen, followed by its reintroduction—in an organ stimulates white blood cells to release oxygen free radicals. The radicals then start the inflammatory response.

In a double-blinded study, Dr. Bennett-Guerrero and his team are testing whether antioxidants given to higher risk patients during surgery can reduce complications. Preliminary results, obtained after the study was unblinded with regard to blood levels only, show people getting the drug have higher blood levels of protective antioxidants. "Whether higher antioxidant status means lower complications has yet to be determined," Dr. Bennett-Guerrero says.