February 17, 2009 — In a neonatal intensive care unit, absolutely nothing is taken for granted. The most sensitive and ingenious medical technology ever devised is dedicated to saving the tiny children swaddled in their incubators, yet the best efforts of expert nurses and physicians sometimes fail to protect them.

The longer the babies stay in the NICU, the higher their risk of developing sepsis, a deadly bacterial infection. By the time their symptoms appear, the children may have already run out of time.

Babies weighing less than three pounds are particularly vulnerable because they can require months of care. One-fifth of these very low birth weight babies develop sepsis, which accounts for 45 percent of deaths among infants living in the NICU for more than a week.

Ten years ago, Dr. Randall Moorman, a University of Virginia cardiologist, and his colleague Dr. Pamela Griffin made an important observation. They found obvious changes in the heart rate patterns of septic infants even before they were clinically ill, with reduced variability and transient decelerations similar to the findings in fetal distress. These distinctive heart rate characteristics, they reasoned, could give physicians the ability to treat infants with antibiotics that much sooner, potentially lessening the severity of the illness and improving survival rates.

After years of testing and clearance from the Food and Drug Administration, eight academic research hospitals, including U.Va.'s School of Medicine, are participating in a National Institutes of Health-sponsored study to further test if heart-rate-characteristics monitoring improves outcomes for NICU babies.

There are occasions, however, when monitoring heart rate characteristics can produce ambiguous results.

"Sepsis is not the only illness that can change these heart rate characteristics," Moorman explained. "In these cases, having another early diagnostic method to use as a tiebreaker would be useful."

Moorman has formed a partnership with Dr. Karen Fairchild, a U.Va. neonatologist; and Jeffrey Saucerman, a U.Va. biomedical engineer, to determine if a blood test for specific cytokines might provide that additional test. Cytokines are signaling proteins released by white blood cells in response to an infection.

Using a mouse model developed by Fairchild, the researchers are focusing on the changing levels of cytokines associated with sepsis, identifying those that are elevated early on and are sufficiently sustained for reliable detection. Saucerman's contribution is to apply quantitative techniques to determine which cytokines are the most important to monitor.

The interdisciplinary team is also trying to determine if cytokines, in fact, alter heart rate variability.

"We already know that sepsis dampens heart rate variability," Fairchild said. "Now we want to know how they are linked."

They propose to use steroids to block the production of cytokines in mice with sepsis and see if normal heart rate patterns are restored.

The immediate goal of this collaborative project is to develop a more selective procedure for diagnosing sepsis than heart rate monitoring alone. The ideal would be to perform a blood test for cytokines when changes in heart rate indicate that sepsis is a possibility. The results from these tests could be produced in just two hours, 25 times faster than the current test to identify sepsis.

The initial phase of the project was supported by the U.Va. Children's Hospital grants program, using donations to the annual Children's Miracle Network Telethon.

Because of the potential to produce advances in neonatal care, the team successfully secured a grant from U.Va.'s Department of Biomedical Engineering that is funded by the $4.5 million Translational Research Partnership Award from the Wallace H. Coulter Foundation. In this partnership with the Coulter Foundation, the department is charged with developing a new model for moving research discovery from the lab to the clinic and the marketplace.

Like many translational research projects, the cytokine study also opens new avenues for basic research.

"Once we draw the connections between sepsis, cytokines and heart rate variability," Saucerman said, "the next step would be to identify the molecular circuits by which cytokines change heart rate variability."