Hospital Workers’ Risks From Drug Spark Debate

A drug used to treat severe lung infections in young children has sparked a controversy within the medical community, because of concerns that it may harm the health-care workers who administer it.

The drug is aerosol ribavirin, and some occupational-health experts say that breathing its mist may lead to birth defects in the workers’ offspring. They say that hospitals should consider warning workers and visitors and restricting the antiviral agent until better delivery systems become widely available.

Two leading medical centers, UC San Francisco and Children’s Hospital in Boston, recently decided to severely restrict the use of aerosol ribavirin, which is widely used in intensive-care units and pediatric wards throughout the country--particularly during the winter.

In addition, a knowledgeable U.S. Food and Drug Administration official said Friday that the agency is “seriously considering requiring” a labeling change for the drug.

The expected change would include warnings about its potential reproductive risk to health-care workers as well as possible reactions, such as irritated eyes, skin rashes and asthma. The details of the warning “have yet to be worked out,” according to the official, who declined to be quoted by name.

Some pediatricians and officials of ribavirin’s manufacturer, ICN Pharmaceuticals Inc. of Costa Mesa, say the worries of critics are overstated. They argue that curtailing the drug may deny a potentially beneficial therapy to critically ill infants.

But the concern about ribavirin has been heightened by recent studies in San Francisco and Cincinnati showing that hospital personnel may be exposed to what the researchers said were much higher levels of the drug than they consider safe.

“The fears of workers about administering this drug are well founded,” said Dr. Maureen Paul of the University of Massachusetts Medical Center in Worcester. “It causes very worrisome reproductive effects in animals of both sexes. We do not have adequate controls in place in hospitals to prevent excessive exposures to workers.”

‘Unsafe Level’

Paul, an assistant professor of obstetrics and gynecology and occupational health who is an expert on reproductive risks in the workplace, said that amounts of ribavirin that would be undetectable in the bloodstream “would still exceed a safe level for workers.”

Although ICN has never issued a formal, written warning, Dr. Leon J. Lewandowski, the company’s vice president of medical affairs acknowledged in an interview that, based on available information, “it was most prudent that pregnant women not be exposed to the drug.”

ICN’s physician information materials about ribavirin, which were reviewed by The Times, do not include any warning about potential reproductive risks of the drug for health-care workers. For example, a 1987 instructional videotape prepared by the company states that the drug “is safe for health professionals.”

When asked why ICN has not issued a formal warning, Lewandowski replied that because the company did not feel that the data were “clear cut,” it’s role was to provide information to health-care workers and hospitals, not to tell them what to do.

Reports Not Mentioned

ICN’s informational materials also do not include mention of about 40 reports the FDA and the company have received of apparent reactions to the drug in health-care workers, including damage to contact lenses, headaches and respiratory problems.

Robert Smith, an ICN vice president, downplayed the significance of the reported reactions, saying, “I don’t consider those serious. Do you?

“No question, we are coming down on the side of safety,” Smith said. “The company takes the position that we don’t want to endanger anybody. (But) there has got to be some evidence that you are endangering anybody before you can make a statement that you are.”

ICN officials also said they have developed a new, potentially safer, delivery system for ribavirin and are testing a commercially available protective mask that may help shield hospital personnel.

‘Significant’ Concerns

At present, however, the concerns for exposed individuals are “significant” and exemplify a more general problem, said Dr. Kenneth W. Kizer, director of the California Department of Health Services. “These new potent agents save lives on the one side but on the other side they have some dangers. There are options (to minimize worker exposure) and we should be striving to make the work environment as safe as possible.”

Last August, Kizer advised the state’s hospitals to consider offering “alternative job responsibilities to female health-care workers who are pregnant or male and female workers attempting to conceive” so that they could avoid exposure to aerosol ribavirin. In December, he asked the FDA to “formally” review the occupational health risks of the drug.

Aerosol ribavirin was approved by the FDA in December, 1985, to treat life-threatening cases of respiratory syncytial virus infection, which is the most important cause of lung infections in infants. Since then, it has been used to treat about 40,000 patients, about 80% under 18 months of age, according to ICN statistics.

The aerosol is designed to speed the drug to the lungs, where the infection resides, while minimizing potential toxic effects to the child, such as anemia.

Fine Mist

The drug is administered as a fine mist, commonly through a breathing mask or in an oxygen tent, for between 12 and 18 hours a day. The child’s nurse and respiratory therapist are unavoidably exposed to medication fumes that escape from the delivery system. If the child is in an open ward, as opposed to a private room, additional personnel may be exposed as well.

A typical course of treatment lasts between three and seven days and adds $500 to $700 a day to the cost of hospital care.

Ribavirin has also been tested, in pill form, as an experimental therapy against the human immunodeficiency virus, the cause of AIDS, and is available in some foreign countries as a treatment for a variety of viral diseases in addition to respiratory syncytial virus, such as hepatitis, the flu and Lassa fever, a life-threatening tropic disease.

Although there are no human data, ribavirin is known to cause birth defects as well as testicular atrophy in laboratory animals. This toxicology data are part of the written prescribing information doctors receive with the drug, as is a warning that it not be used as a treatment for “women or girls who are or may become pregnant during exposure to the drug.”

ICN officials explained that it is probably safe for care-givers and hospital visitors to breathe relatively small concentrations of ribavirin, as compared to the higher levels used to treat patients. They said the company has received no reports of birth defects that may be related to the drug.

Outdated Information

But to support this view, ICN officials have cited outdated information about the use of ribavirin at Children’s Hospital of Boston, a world-renown Harvard Medical School affiliate.

An October, 1988, ICN brochure quotes a January, 1988, letter in a medical journal by Dr. Kenneth McIntosh, the hospital’s chief of infectious diseases, as a “potential guide” for other hospitals. The letter states that “ribavirin administration is probably completely safe for caretakers”

In fact, McIntosh said in an interview with The Times, Children’s Hospital of Boston “suspended” use of ribavirin last fall because of safety concerns and has so informed ICN officials. McIntosh said he had become “more concerned about the safety issues” because of the new evidence “that the levels of ribavirin in the air are high.”

When asked about the brochure, Jack Sholl, an ICN vice president for public relations, said, “If (McIntosh) has changed his position, then I suppose yes, indeed, this (brochure) should probably reflect it.”

Unneeded by Majority

The debate about ribavirin’s safety is complicated by the fact that the vast majority of children with respiratory syncytial virus do not need the drug.

“We are not talking about the cure for AIDS,” McIntosh said. “Most children with respiratory syncytial virus get better on their own, most children with severe (cases) also get better with good supportive care (such as nursing care, oxygen and intravenous fluids). The impact of ribavirin on mortality is something that is not completely demonstrated.”

McIntosh added that “while there may be exceptions,” Children’s Hospital of Boston had decided “that we would in general not be using ribavirin until the system for delivery is improved.”

On the other hand, at Memorial Miller Children’s Hospital in Long Beach, the second busiest pediatric facility in California, 30 to 40 infants will probably be treated with aerosol ribavirin during this winter’s respiratory syncytial virus season. Health-care workers who are pregnant or attempting to conceive receive alternate job assignments, said Dr. Melvin Marks, the hospital’s medical director and vice chairman of the department of pediatrics at UC Irvine.

‘Disservice’ to Patients

“We feel that it would really be a disservice to our patients to withhold a potentially beneficial therapy, particularly if it was for reasons of putting our own safety ahead of that of the patient’s benefit,” Marks said.

He added: “It is a very safe drug in patients, which is why it should be a safe drug in personnel. . . . We must not let our anxieties and fears of potential risks as opposed to actual risks unduly influence our therapeutic decisions.” Marks acknowledged that he has received payments from ICN for educational lectures about respiratory syncytial virus and its treatment.

Most children contract respiratory syncytial virus during the first years of life. The majority have mild cases, characterized by symptoms such as fever, cough, nasal congestion and wheezing.

About 1% to 2% of the respiratory virus cases--estimated to be between 50,000 to 90,000 a year--are serious enough to require hospitalization, according to Dr. Larry Anderson, a viral disease expert at the U.S. Centers for Disease Control in Atlanta.

Severe Category

Only a minority of these hospitalized children fall into the severe category for which aerosol ribavirin is intended. The virus is estimated to contribute to between 2,000 and 4,500 deaths each year, primarily in children under age 4 with underlying heart, lung or immune system ailments, Anderson said.

The California Department of Health Services began its study of aerosol ribavirin in 1986, after being contacted by health-care workers concerned about the potential health hazards of breathing the drug.

From December, 1986, to March, 1987, a team of researchers led by Dr. Robert Harrison of the department’s Occupational Health Surveillance and Evaluation Program in Berkeley studied exposure levels of aerosol ribavirin in the pediatric intensive-care units at four San Francisco Bay Area hospitals.

Their results, published in the Sept. 16, 1988, issue of the federal government’s Morbidity and Mortality Weekly Report, showed that nurses were exposed to ribavirin dose levels that were 30 to 40 times higher than what researchers said was the recommended safety threshold for worker exposure to substances that can cause reproductive problems.

Use Restricted

Based on the results of this study, UC Medical Center San Francisco last November restricted ribavirin use to infants so ill that they must receive mechanical ventilation and decided to offer pregnant health-care workers alternative job responsibilities.

In early 1988, the National Institute for Occupational Safety and Health confirmed the findings of the San Francisco study. Institute scientists found that nurses at Children’s Hospital Medical Center in Cincinnati were routinely exposed to levels even higher than those found in the San Francisco study, according to a copy of the results made available to The Times.

ICN officials disputed the meaning of such data. They pointed out that the San Francisco study detected ribavirin in the blood of only one of the 10 health-care workers tested and that an earlier, company-sponsored study at Children’s Hospital National Medical Center in Washington had failed to detect the drug in the blood of 19 nurses. (The NIOSH researchers did not collect blood samples).

“I can’t accept the argument that if you can’t measure it, it is a problem anyway,” Smith of ICN said. “That is just . . . not good science. I am personally very reassured by the fact that you can’t find it in people’s bloodstreams.”

View Disputed

This view was disputed by Harrison of the California Department of Health Services, who has played a key role in focusing attention on the ribavirin safety issue. He said blood and urine tests “are probably not sensitive enough to indicate exposure at the air concentrations needed to maintain an appropriate margin of safety.”

Company officials also claimed in an interview that their new “aerosol delivery hood” and the protective mask, the 3M Brand “9970 high efficiency respirator,” are capable of reducing exposures to ribavirin to below recommended safety thresholds. They said that the delivery system, which is designed to keep ribavirin from escaping into the patient’s room, is just being made available to hospitals and that the mask is still being tested.

These claims were also disputed by Harrison, who said that in meetings he has had with ICN officials no data had been produced to show “that the proposed aerosol hood and the use of masks can adequately protect workers.”

He added: “I don’t think we should wait for the babies with birth defects. We should take a public health approach and prevent that in the first place.”