St. Louis Children's Hospital
January 4, 2008

Two pediatric patients undergoing kidney dialysis experience sudden, life-threatening allergic reactions. Their eyes, lips and tongues begin to swell, raising their heart rates and dropping their blood pressures dangerously low.

After dialysis staff treat the children with medication to relieve their symptoms, nephrology unit medical director Anne M. Beck, MD, associate professor of pediatrics, and her staff contact pediatric infectious disease specialist Alexis M. Elward, MD, assistant professor of pediatrics, who quickly begins looking for the cause.

"I was most suspicious it was a chemical reaction because it seemed to hit as soon as the patient's blood hit the dialyzer tubing," Elward says.

But records indicate two similar incidents at the hospital in November of 2007.

Situation Teams Activated
January 4, 2008

Elward, along with Marilyn L. Jones, RN, MPH, director of Interventional Epidemiology Programs for Patient Safety and Infection Prevention for BJC HealthCare, activate BJC HealthCare's Epidemiology and Patient Safety Consortium, with a "SWAT team." The group includes an epidemiologist, data analyst, database manager and other health care professionals.

"The 'SWAT team' is one thing that makes BJC positively unique," says Jones. "We have the ability to assist our BJC hospital teams whenever the safety of patients is of concern. The team is rapidly deployed to figure out control measures and find answers."

St. Louis Children's Hospital also activated its team, which includes physicians, nurses, risk management, materials management and information systems.

24/7 Command Center
January 7, 2008

With Elward and Jones at the helm, the teams set up a command center from which they work around the clock during the next week. They research the lot numbers of medications, the kind of tubing used and the water sources into the dialysis machines, and they review policies and procedures.

In a literature search of similar incidents at other dialysis centers, Elward finds that the anti-clotting drug heparin was a possible cause of allergic reactions. But the symptoms were different from those experienced by the patients at St. Louis Children's Hospital. She and the team post warnings about the reactions on several pediatric and dialysis listservs, report the event to the Food and Drug Administration (FDA) and contact the Centers for Disease Control (CDC) and the Missouri Department of Health and Senior Services.

FDA Reps at Medical Center
January 7, 2008

Food and Drug Administration representatives arrive on site in St. Louis to take heparin samples.

Elward contacts Baxter International, which manufactured the heparin used at St. Louis Children's Hospital, to inform them of the problem.

Dialysis must continue and so the clinic staff leave nothing to chance. They change all equipment, water sources and medications — including using heparin from a different manufacturer — and relocate the clinic within the hospital.

"We were thinking that we really needed to get an answer as quickly as possible, because dialysis is not something that can be postponed for very long," says Elward. "We took every possible step to protect our patients."

But still, there was no clear understanding of the root of the problem.

Centers for Disease Control
January 14, 2008

At the request of the Missouri Department of Health and Human Services, a CDC officer arrives at the command center to assist in the ongoing investigation at St. Louis Children's Hospital. In the nearly two weeks since the CDC first posted warnings on a national listserv of dialysis units, dozens of phone calls and e-mails from other centers nationwide reported patients with similar reactions.

"It was great to have the input of the CDC," says Elward. "We knew we were statistically underpowered to determine a cause via an epidemiological study. It was reassuring that the CDC was asking the same questions we were asking. We had brilliant people from the medical center, the CDC and the FDA wrapped around this, working day in and day out."

Heparin Recall
January 17, 2008

Baxter International voluntarily recalls nine lots of heparin based on reports of reactions it had received from dialysis clinics, operating rooms and critical care facilities nationwide.

The FDA and Baxter consider removing additional lots of heparin. But, given the drug's widespread use, this seems potentially more disruptive and dangerous to patients than the likelihood of widespread adverse reactions.

By February 28, the FDA concludes there is sufficient capacity on the part of other suppliers that Baxter's recall will not jeopardize access to the drug. Baxter voluntarily recalls its remaining lots of heparin.

Heparin's active ingredient itself does not escape scrutiny. Producers of it are ordered to verify the quality and safety of their ingredients.

This action turns out to be critical.

Protecting patients, solving a mystery: Pediatric infectious disease specialist Alexis M. Elward, MD, and nurse Marilyn L. Jones, RN, MPH, headed the hospitals' "SWAT team" as they unraveled clues related to a tainted dialysis drug.

Turns out, it wasn't the heparin after all.

Heparin is a blood thinner commonly used in patients undergoing kidney dialysis, some types of cardiac surgery, and for treatment or prevention of other serious medical conditions. It is derived from pig intestines processed primarily in small plants in China. A cheaper substitute made from animal cartilage, called oversulfated chondroitin sulfate, imitates heparin so closely that it is not recognized by routine testing. Thus this less expensive product could escape normal detection. But oversulfated chondroitin sulfate activates enzymes that cause the body to make inflammatory mediators that can lead to symptoms such as low blood pressure, abdominal symptoms and shortness of breath.

Jones says that at the time of the crisis they didn't know it would turn into an international investigation.

"It really comes down to the astute clinicians saying, 'This is very unusual,'" says Jones. "It was our ability to quickly figure out what wasn't causing it that helped us determine that these reactions were unusual. If the FDA and CDC hadn't been called, this could have gone on much longer."

Elward agrees. "We have a good infrastructure in terms of our ability to do an investigation within the medical center. We had resources at our fingertips and were able to use the partnership between Washington University and BJC to review the literature, contact the right people, do intense data collection from charts and look at this very systematically from an epidemiologic perspective. We also have a good relationship with the local health department and federal authorities and were able to get in touch with them immediately."

"Dr. Elward's swift launch into a cause for these reactions at St. Louis Children's Hospital was exemplary," says Alan L. Schwartz, PhD, MD, the Harriet B. Spoehrer Professor and chairman of the Department of Pediatrics. "Her attention to detail helped the state and federal authorities in their investigations and likely protected other children receiving dialysis from having similar reactions."

Gregory A. Storch, MD, the Ruth L. Siteman Professor of Pediatrics and director of the Division of Infectious Diseases, says the discovery is one of the most important outcomes of an infection control investigation in years.

Worldwide reaction — alerts, safeguard procedures, analysis of the problem and published findings — helped make dialysis safe again for patients such as Corbin Burdick, seen here with Kira Geile, RN, in the dialysis unit at St. Louis Children's Hospital.

"The success of the investigation was no accident," Storch says. "It reflected Dr. Elward's extreme commitment to patient safety and the skill and strength of the medical center's infection- control teams. Through tenacious investigations, Alexis Elward and her team uncovered a situation that has profound ramifications, raising questions about international production of pharmaceutical products and the role of the U.S. Food and Drug Administration."

The reactions to contaminated heparin, as well as recent incidents of melamine tainting dairy products, led to the establishment in November 2008 of FDA offices in China that will work to ensure the quality of food, drug and feed imports.

"The events in the dialysis unit at St. Louis Children's Hospital could easily have been passed over," says Storch. "Instead, Alexis, Anne, Marilyn and others recognized the unusual nature of the events and doggedly sought an explanation. A very strong team, their efforts were in the best tradition of 'shoe-leather' epidemiology."

Heparin cleared The likely catalyst of the outbreak was not heparin, but a contaminant called oversulfated chondroitin sulfate.

Study reveals culprit in dialysis reactions Alexis M. Elward, MD, and Marilyn L. Jones, RN, MPH, are co-authors of a paper that appeared in the December 18, 2008 New England Journal of Medicine in which federal agencies assert that a contaminant called oversulfated chondroitin sulfate may have been responsible for the outbreak of allergic-type reactions that occurred in dialysis patients receiving heparin in clinics nationwide in late 2007 and early 2008. Their co-authors include researchers from the Centers for Disease Control and Prevention (CDC), Massachusetts Institute of Technology (MIT) and the U.S. Food and Drug Administration (FDA), among others. Of 152 adverse events studied, 99 percent of reactions occurred in patients who may have received oversulfated chondroitin sulfate-contaminated heparin. Of those patients, more than 92 percent had reactions within 30 minutes after receiving heparin manufactured by Baxter International Inc., which voluntarily recalled nine lots of its heparin from the market. Once the lots were recalled, reports of reactions dropped considerably; the last reaction reported to the CDC occurred on January 31, 2008. The exact lot of heparin given to each patient studied could not be determined in every case because health care facilities do not routinely record the lot number of heparin at the time of administration. The contaminant was present in nearly every instance when a patient reacted to dialysis treatment. Researchers from MIT tested unopened vials of heparin from nine lots linked with allergic-type reactions from facilities reporting cases. Seven of the Baxter heparin lots contained oversulfated chondroitin sulfate. The findings also revealed that more than half of all patients that had a reaction and each of the four patients at St. Louis Children's Hospital had preexisting allergies to different drugs. "We wondered about medication allergies as a predisposing factor that those patients may have already had some activation of their immune systems, so if they saw something that was a contaminant, they would be primed to have a more severe reaction," Elward says. The researchers reported in the New England Journal of Medicine paper that they found no single clinical factor that was closely associated with developing an allergic-type reaction from oversulfated chondroitin sulfate-contaminated heparin. Some of the factors that may have contributed to the reactions include age and immune status of the patient, medication dose and route, and the percentage of oversulfated chondroitin sulfate and its reaction with other biologic substances.