Anesthesia in children linked to learning disabilities?

Boston-The jury is still out on the effects of anesthesia in children who undergo surgery at a young age, according to Constance S. Houck, MD. Multiple animal studies have demonstrated neuroapoptosis and long-term learning deficits in young animals after administration of general anesthesia, but population-based studies in humans have been far less clear.

A higher incidence of learning disabilities has been found in a cohort of children who have had multiple anesthetics before the age of 4 years but it is unclear whether this is due to effects of the anesthetic or other underlying medical issues that necessitated the multiple surgeries, said Dr. Houck, senior associate in perioperative anesthesia, Children’s Hospital Boston and associate professor of anesthesia, Harvard Medical School, Boston.

Without definitive studies suggesting a viable alternative, no changes in practice are currently proposed although there is an urgent need for more studies, she added.

The possibility that anesthesia can cause subtle neurologic changes in young children has been a concern for some time. Over the past 10 years, bits of information from various studies have caused concern. Recent studies have implicated both inhaled and intravenous anesthetics as potentially neurotoxic to young animals, Dr. Houck noted.

An important animal study conducted by Jevtovic-Todorovic and associates and published in the Journal of Neuroscience (2003;23:876-882) found that exposure of 7-day-old rat pups to commonly used anesthetic agents resulted in widespread neurodegeneration and learning deficits. These changes were not seen in older rats that received the same anesthetic. The pups received one dose of midazolam and were exposed for 6 hours to oxygen, nitrous oxide, and isoflurane.

Behavioral testing of learning and memory were performed when the rats were 3 months old. Investigators found significant and extensive neuroapoptosis after general anesthesia.

“More importantly, the investigators also found learning deficits in the rats that had been exposed to the anesthetics,” Dr. Houck said. “These results were very concerning.”

The anesthesia community initially explained the results by crediting the findings to a species-specific toxicity and differences in monitoring practices between this animal study and human care.

There was also a question about a comparison of the ages of the animals being studied with that of human children. However, since then numerous animal studies of anesthetics that are commonly used in children have reported neuroapoptosis and learning deficits in infant rats, mice, guinea pigs, piglets, and primates, Dr. Houck noted.

A recent population-based retrospective birth cohort study by Wilder and associates (Anesthesiology. 2009;110:796-804) was the first to show that the effects of anesthesia on young children may be a real concern. A total of 5,357 children from Olmstead County, MN, were included, of whom 593 children had had a general anesthetic before 4 years.

The study found that if the children received only one anesthetic, there was no increased risk of learning disabilities. However, if children received two or more anesthetics before age 4 there seemed to be an increased risk of a learning disability.

In addition, the risk increased with longer cumulative duration of anesthesia exposure, Dr. Houck said. A follow-up study from the same group recently published in Pediatrics (2011;128:e1053-1061. Epub 2011 Oct 3) that included a more rigorous evaluation of underlying health status confirmed this higher risk of learning disabilities in children who received multiple anesthetics before age 2 but showed no increase in behavioral abnormalities.

Another study published by DiMaggio in the Journal of Neurosurgical Anesthesiology (2009;21:286-291) retrospectively evaluated a cohort of 228,961 children. Of these, 383 underwent surgery to repair a hernia before age 3.

“The incidence of a behavioral or developmental disorder in the children exposed to anesthesia was 20.6 cases per 1,000 compared with 6.6 cases per 1,000 in the children not exposed to anesthesia,” Dr. Houck said. “When the data were adjusted for birth weight, age, gender, race, and medical service level, the children who were exposed to anesthesia before the age of 3 years were twice as likely to [have] a developmental disorder [diagnosed].”

A study from the Netherlands by Bartels and associates (Twin Research and Human Genetics. 2009;12:246-253) of 1,143 monozygotic twins identified 71 pairs of twins where one had received anesthesia and the other twin had not. The findings indicated that the twins who had been exposed to an anesthetic agent before age 3 had lower educational achievement scores at age 12. However, the twins who had not been exposed to an anesthetic had the same learning-related outcomes at age 12, according to Dr. Houck.

“This suggested that factors other than anesthesia might explain these differences,” she said.

Similarly, a recent Danish study by Hansen and associates (Anesthesiology. 2011;114:1076-1084) looked at 2,689 adolescents who had undergone inguinal hernia repair before 1 year of age. When the adolescents were compared with 14,575 matched controls, and the analysis was controlled for gender, birth weight, and parental age, there was no difference in the academic achievement scores between the two groups.

A follow-up study in Anesthesia and Analgesia (2011;113:1143-1151) by DiMaggio, et al. evaluated the twins in their previously analyzed cohort. Of 10,450 twins, the investigators found 138 pairs in which one twin had had an anesthetic before 3 years of age and the other had not. They found that most of the twins did not have any brain developmental issues. When they looked at one twin of a pair with a development issue, there was a split between children who had been and had not been exposed to an anesthetic agent.

“There are clearly twin studies that are finding that the effects of a single, brief anesthetic in young children may not be the concern that it was thought to be initially,” Dr. Houck said. “However, there still remains concern because none of these studies has looked at the effects of multiple and prolonged anesthetics. Longer duration of anesthesia may be the important issue.”

SmartTots (Strategies for Mitigating Anesthesia-Related Neuro-Toxicity in Tots) is a partnership between the FDA and the International Anesthesia Research Society to provide research support for investigators looking at neurotoxicity in children. There are four currently funded studies including the Pediatric and Anesthesia Neurodevelopment Assessment (PANDA) and GAS studies, the Rochester Epidemiology Study, and the Arkansas Children’s Study.

The PANDA study is evaluating a multi-institutional historical cohort of 500 children who underwent inguinal hernia repair before the age of 3 and comparing them with siblings who are within 3 years of age who have not had surgery. These children will undergo standardized neurocognitive assessments at 6 and 11 years of age.

The GAS Study is a multi-institutional prospective, randomized, controlled study of about 700 children scheduled for inguinal hernia repair between 26 and 60 weeks gestational age. The children are randomly assigned to either general anesthesia or spinal anesthesia and will undergo neurodevelopmental testing at 2 and 6 years of age. Thus far, about 400 children have been enrolled.

The cohort in the Rochester Epidemiology Study is currently being expanded to include children who have undergone surgery more recently. The original cohort includes only children who had surgery in the late 1970s and early 1980s.

A number of recent animal studies have shown that some drugs, such as melatonin, lithium, and dexmedetomidine, the experimental anesthetic xenon, and hypothermia can reduce neuroapoptosis, according to Dr. Houck.

Dr. Houck has no financial interest in the subject matter. She is a member of the advisory board of SmartTots.

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