Common anesthetics appear safe for developing fetal brain

March 09, 2005

DURHAM, N.C. - An anesthetic regimen commonly used during surgery on pregnant mothers appears to have no negative effects on the developing brain of the fetus, according to a new study on sheep conducted by Duke University Medical Center researchers.

Furthermore, the researchers found, the use of this regimen to produce general anesthesia appears to improve the oxygenation of the fetal brain, according to their novel system for measuring cerebral oxygenation in the developing fetus.

These findings are an important step toward better understanding this issue, the researchers said, since a study in new-born rats published in 2003 reported that exposure to various anesthetic agents caused neurodegeneration in the developing rat brain. However, the Duke researchers said that the current study may be more realistic, since it is was conducted under circumstances that more closely parallel that which humans would experience.

"The results of this investigation suggest that the moderate inhalation anesthetic exposure during pregnancy may not be deleterious to the fetus," said lead researcher James D. Reynolds, Ph.D., research director of women's anesthesia at Duke. The results of the Duke study were published March 9, 2005, as an advanced on-line publication of the Journal of Cerebral Blood Flow and Metabolism.

"These types of studies are very difficult to conduct in humans, since you can't do the invasive type of monitoring you can in animal models, and it is difficult to separate the effects of the anesthesia from the underlying reasons for the surgery," Reynolds said. "So we felt that in order to come as close as possible to what might be expected in humans, we had to do something new."

General anesthesia, which typically involves a combination of drugs, renders the patients temporarily unconscious during the surgery.

The earlier study -- the results of which led to much discussion in the anesthesia community -- involved putting newborn rat pups in a static chamber, where they inhaled various anesthetics. The results of those studies showed evidence of increased apoptosis, or programmed cell death, in developing nerve cells.

For their new experiments, the Duke team developed a model using pregnant sheep. When the sheep fetus was approximately 17 weeks old - an age that approximates a third-trimester human pregnancy - the researchers exposed the mother to a three-drug anesthetic combination commonly used to produce general anesthesia. The exposures lasted four hours, a length of time that would encompass most surgeries conducted on pregnant patients.

"We found that four hours of maternal general anesthesia produced an initial increase in systematic oxygenation in the fetus, as well as a sustained increase in oxygenation in the brain," Reynolds said.

The researchers could document cerebral oxygenation in real time because of a system they optimized for fetal applications. The technique, called near-infrared spectroscopy, was originally conceived in the 1970s by Duke faculty member Franz Jobsis.

Light in the near-infrared range can easily pass through skin, bone and other tissues. However, within these frequencies of light, the oxygen-carrying molecules within red blood cells known as hemoglobin absorb light to an extent based on their oxygen content -- giving the researchers a reliable indicator of cerebral oxygenation. Researchers place a fiberoptic probe against the skull of the fetus to measure the changing oxygenation levels of blood circulating in the brain, Reynolds said.

Reynolds said that the increase in oxygenation in the fetal brain is likely due to isoflurane, one of the three commonly used agents, which induced reductions in oxygen metabolism along with increases in cerebral blood flow. Isoflurane is known to produce these actions in the adult brain but it had not been appreciated that such effects could also occur in the fetal brain, he said.

Besides the oxygenation studies, the researchers also examined the brain tissue from the exposed fetuses and found no evidence of neurodegeneration or apoptosis.

The researchers said the timing of the exposures to anesthetic agents is an important consideration when determining how closely animal models reflect what may occur in humans. The brains of different animals, as well as humans, are more vulnerable to insult at different times in their development.

"Most of the major synapse formation and neuronal development of the rat is a post-natal event, peaking at about day seven after birth," Reynolds said. "In sheep however, the brain growth spurt occurs toward the end of gestation, which in many respects is more similar to what happens in humans, where development occurs both before and after birth."

Reynolds said that since it is ethically questionable and technically difficult to do exposure studies directly in humans, large retrospective epidemiological studies are needed to determine whether there are any cognitive or development issues in children or young adults whose mothers received general anesthesia for surgery.

The most common surgeries that pregnant human mothers undergo are abdominal, such as appendectomies or gall bladder removals, Reynolds said. These procedures are more common in women than men, and they can be especially difficult to accurately diagnose in pregnant women, since many of the symptoms of these disorders are similar to those of pregnancy.

Reynolds said that the laboratory's future investigations will focus on determining the upper limits of anesthetic exposure, as well as developing a better understanding of the combined effects of anesthesia and surgical manipulation on physiological changes in the fetus. His research group is also investigating the effects of the gases used to "inflate" the abdomen to enable the use of minimally invasive laparoscopic procedures.
The research was support by the National Institutes of Health, the Howard Hughes Medical Institute, the Duke Anesthesiology Research Fund and the Duke Endosurgery Center.

Other members of the research team are Rebecca McClaine, Sebastian de la Fuente, Roberto Manson, John Booth, William White, Kurt Campbell1, Deborah McClaine, all of Duke; Kenichiro Uemura, Hiroshima University, Japan; Paul Benni, CAS Medical Inc.; and Steve Eubanks, formerly of Duke and now chair of the Department of Surgery at the University of Missouri.

Duke University Medical Center

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