Bench to Bedside | August 2016

Study Results Offer Reassurance on Anesthesia Safety for Young Children

A young child gives a groggy wave to his parents as he is wheeled into the operating room suite. They are confident that he is in the good hands of the surgical and anesthesiology teams, but a worry still lingers. Will the anesthetic agents used during the procedure have long-term effects on their child’s developing brain? Results from a large, comprehensive study that looked at the neurodevelopmental risks of a single anesthesia exposure in early childhood may offer them some reassurance.

About 2 million children younger than 5 undergo general anesthesia or deep sedation each year for surgical procedures such as tonsillectomy and hernia repair, and diagnostic procedures such as imaging studies. Unlike some adult surgeries, most pediatric procedures cannot be delayed for a significant length of time. These necessary medical procedures would not be possible while a child is awake, yet many questions remain about pediatric anesthesia and risks of brain abnormalities if the exposure occurs before a certain developmental age.

“It is potentially a significant public health issue that is important to look at,” said Francis McGowan, MD, endowed chair and director of Pediatric Anesthesiology Research at The Children’s Hospital of Philadelphia, who helped to design and conduct the Pediatric Anesthesia Neurodevelopment Assessment (PANDA) study along with Lynne Maxwell, MD, senior anesthesiologist at CHOP.

Many researchers previously have examined the possible association between early-life anesthesia exposure and neurodevelopmental outcomes in animals, accumulating more than 500 studies focused on this topic. Some of the results suggest that when very young animals are given various drugs used for anesthesia, the animals developed learning and memory problems and changes in their brain related to brain cell death and other abnormalities. However, scientists do not have convincing evidence that similar outcomes occur in human infants.

“The animal studies are compelling, but issues remain related to species differences, the dose and duration of the animal anesthetic exposure that was necessary to produce injury, whether there is a developmental window of vulnerability, and how long it’s open if there is one,” Dr. McGowan said.

Another important distinction, Dr. Maxwell pointed out, is that the study animals exposed to anesthesia are not experiencing any pain. Scientists do not know if the painful stimulus during surgery either increases or decreases risks of harm from the anesthetic agents. They also are uncertain if the dosages given to animals in the studies are comparable to dosages administered to children.

As basic scientists have been struggling with these unknowns, epidemiologists have tried to give a larger view by analyzing patient datasets to determine if children who received general anesthesia were more likely to have developed deficits in brain development when compared to children who have not had such exposure. Their efforts have produced mixed results, and some of the clinical studies did not account for certain factors known to influence cognitive development, such as socioeconomic status and parental education. The researchers also were not able to sort out details about why the children had surgery or specifics about their general health.

Meanwhile, the lack of definitive research findings has been unsettling for the pediatric anesthesia and surgical communities as well as for parents.

“Increasingly, parents will call because their children are scheduled for surgery, and they’ll ask what should be done to minimize the chance of having problems,” Dr. Maxwell said.

The PANDA study team, which was comprised of neuropsychology, neurodevelopment, and anesthesia experts from five institutions, recognized the imperative need to rigorously evaluate the neurodevelopmental effects of anesthesia exposure in early childhood. They designed the study to include healthy children who were exposed to the same type of anesthetic agents for a duration of 120 minutes or less when they underwent inguinal hernia surgery before age 36 months. They chose this age range because it includes the crucial period of rapid brain development in young children.

The investigators compared this group to a cohort of their healthy siblings with no anesthesia exposure. Since the 105 sibling pairs lived in the same households and were within three years of age of each other, the investigators were confident that they shared the same socioeconomic and parental education status. Most of the study participants were boys, since this type of hernia repair is less frequently needed for girls.

Using a comprehensive battery of neurodevelopmental tests performed later in childhood, the PANDA researchers showed that there was no difference in IQ scores between the two groups. The results also indicated no difference in mean scores of memory, attention, visuospatial function, executive function, language, motor and processing speed, or behavior.

“An important aspect of this study is the age of neurodevelopmental testing in these children was between 8 and 15,” Dr. McGowan said. “That is when these tests are most reliable. If something was going to appear as a problematic signal, these children were at an age when you could be relatively confident of the results.”

While the PANDA study results are encouraging, Dr. McGowan and Dr. Maxwell said this does not provide a definitive determination that all young children are unlikely to have cognitive problems following exposure to anesthesia. More clinical research needs to be done to see if certain subgroups of the pediatric population, such as those exposed to repeated or prolonged durations of anesthesia, could be especially vulnerable. And since most of the PANDA study participants were boys, future studies need to take a closer look at the effect of anesthesia on cognitive function in girls. In the laboratory, basic scientists need to better understand the mechanisms of neuronal injury in young animals exposed to anesthesia and then determine if those mechanisms apply to humans.

“CHOP is actively engaged in research projects that cover the whole spectrum — from animal studies to translational research to clinical epidemiology to testing novel anesthetic agents — in order to address these important questions,” Dr. McGowan said.

Findings from the PANDA study appeared online in the Journal of the American Medical Association. Study sites included CHOP; Columbia University Medical Center, New York; Boston Children’s Hospital; and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville. Dr. McGowan also is a professor of Anesthesiology and Critical Care at the Perelman School of Medicine at the University of Pennsylvania, and Dr. Maxwell is a professor in the same department.


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