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Common Anesthetics Appear Safe for Developing Fetal Brain

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Duke Health News 919-660-1306

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.

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