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http://www.nytimes.com/2002/08/28/health/28TISS.html

Surgeons Are Warned About Heart Valves

By SANDRA BLAKESLEE

wo weeks ago, the Food and Drug Administration ordered CryoLife Inc. of Kennesaw, Ga., a leading supplier of donated human tissue, to recall all tissue used in orthopedic surgery — ligaments, tendons, cartilage and other soft tissue popular for repairing knees and joints. The agency said CryoLife could not assure that its tissues, taken from donated cadavers, were free from dangerous bacteria and fungi.
But human heart valves are a different story.

CryoLife has about 70 percent of the nationwide market in these valves, and while it uses the same process for removing microbes from them as from other kinds of tissue, the F.D.A. is only warning heart surgeons to watch for bacterial or fungal infections in patients who have received CryoLife valves. The agency has advised doctors whose patients await surgery to consider using valves from other companies.

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CryoLife says it is appealing the F.D.A.'s recall of its tissue and has not made a statement concerning the notice to surgeons about its heart valves. Even so, the disparity between the treatment of orthopedic tissue and heart valves reflects the nation's patchwork system of regulating companies that provide human tissue for use in transplants.

Dr. Dan Schultz, deputy director of the F.D.A.'s office of device evaluation, said that different branches of the agency regulate the two types of tissue, though the two branches jointly inspect tissue processors.

In recent months, CryoLife tissues have been implicated in one death and at least 25 serious infections following routine knee surgery. The federal Centers for Disease Control and Prevention is investigating several cases of bacterial or fungal infections in heart valves reported by physicians and patients since March. It would not say what companies made the valves in these cases, but in a notice sent to heart surgeons last Wednesday, the F.D.A. said at least at least two valves were CryoLife's.

CryoLife, which has provided human heart valves for 41,000 patients since 1984, is the only company whose heart valves the drug agency and the disease control center acknowledged investigating.

The government has not established strict guidelines for harvesting or processing human tissue, whether heart valves or soft tissue. The F.D.A. requires processors to follow written procedures, but the processors for the most part make up their own procedures or follow guidelines from a voluntary trade organization. The agency is developing new regulations for the human tissue industry, but final rules have not been written.

The American Association of Tissue Banks has drawn up technical guidelines for handling tissues and regularly inspects its members' operations. But CryoLife does not belong to the group and has its own procedures for handling tissue, which it does not disclose.
Human heart valves unquestionably save lives, and thousands of Americans have received them in the last 15 years. But health authorities said they could not tell how many recipients developed infections from their transplants.

Many valve recipients are elderly, and when an older person has a stroke months after heart surgery, doctors are likely to blame a blood clot, not bits of fungus that break off the valve and lodge in the brain.

Ken Alesescu, who received a CryoLife heart valve in July 2001, does not fit that profile. A 50-year-old chiropractor from San Luis Obispo, Calif., he was relatively young and active but had high blood pressure because of a faulty heart valve. His case was first reported last night on the CBS Evening News.

Within a month of surgery to receive the replacement valve, Mr. Alesescu began losing weight, then developed fever, chills and diarrhea, according to his wife, Pam.

Then, in January, he suffered a stroke that paralyzed the left side of his body, and underwent emergency brain surgery to remove a blood clot. In February, a test revealed the heart valve was contaminated with fungus. A new one was implanted, but Mr. Alesescu continues to have a fungal infection throughout his lower spine. Mr. Alesescu is suing CryoLife, contending that the replacement valve caused his illnesses.

The company acknowledged in a statement that "signs of infection" were found on the heart valve after it was removed from Mr. Alesescu. But, the statement added, "There are many potential sources of infection in any surgery," including germs introduced by the surgeon or surgical instruments.

"To our knowledge," it concluded, "no one has shown that the heart valve in question was infected when it was provided to the patient."

David Fronk, vice president for clinical research at CryoLife, said any kind of heart valve, whether synthetic or biological, could carry infections. Moreover, he said, CryoLife has never labeled its products as sterile. It is not possible to guarantee complete sterility, he said.

Mr. Fronk added that the company's own research program showed that rates of infection were very low. Of a sample of 1,200 operations using CryoLife heart valves, 6 or 7 patients developed heart infections.

"This is a tragic consequence of open heart surgery," Mr. Fronk said. "It happens."

According to the American Heart Association, 96,000 Americans had new heart valves implanted last year. Depending on a variety of factors, the patients got heart valves derived from synthetic materials, pigs, cows or human cadavers.

Human valves, or allografts, are clearly best for a small number of patients, said Dr. Timothy Gardner, chief of cardiothoracic surgery at the Hospital of the University of Pennsylvania, but most can be treated with other methods.

Beyond tests for H.I.V. and AIDS, there are few federal safety standards for processing human tissue. And, Dr. Schultz of the F.D.A., said that while hospitals are required to report deaths involving medical devices, few surgeons think of human donor valves as devices.

Assuring that the tissue used for such transplants is uncontaminated is difficult. The cadavers from which the tissue are drawn may contain microbes like bacteria and fungi that can contaminate the tissues. Sterilization can kill microbes, but it can also damage human tissue, sometimes destroying its usefulness.

Once donor tissue is implanted, certain kinds of microbes, under certain conditions, can undergo explosive growth; some release deadly toxins that are difficult to eradicate once an infection occurs.

Most processors test each piece of tissue for microbes when they receive it. If there are signs of contamination, they discard the tissue, said Dr. Marion Kainer, a former epidemiologist at the Centers for Disease Control and Prevention who recently investigated the industry after a 23-year-old Minnesota man died following routine knee surgery.

CryoLife suspended such testing a few years ago, Dr. Kainer said, saying there was no evidence it made tissues safer. CryoLife renewed such testing in May after the centers criticized the decision. CryoLife said that it now discards individual tissues found to be contaminated but processes the rest of the donor's tissues if they appear clean.

Second, to avoid contaminating tissues in the factory, processors generally bathe tissues in an antimicrobial solution and retested. If clean, they are packaged and sold. CryoLife also treats its tissue, usually by bathing it in a solution, but it says its process is proprietary.

In her effort to identify the source of Mr. Alesescu's illness, his wife, assisted by the centers, was able to identify the donor of her husband's original heart valve by a tracking number on its package.

Mrs. Alesescu said the tissue, including the heart valve, first went to a tissue bank, the Midwest Transplant Network in Westwood, Kan. From there, some soft tissue went to a processor in Edison, N.J., the Musculoskeletal Transplant Foundation. The heart went to CryoLife.

The foundation tested the soft tissue, found that two samples were contaminated with an unidentified fungus, and destroyed them, a spokesman said.

CryoLife said it found no evidence of a fungus on the same donor's heart valve after bathing it in an antimicrobial solution. It later sold the product to Mercy Hospital in Sacramento, which operated on Mr. Alesescu. The hospital, also named in Mr. Alesescu's suit, had no comment.

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