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Repeated exposure to general anesthesia did not negatively affect neurobehavioral outcomes among children with cystic fibrosis, the randomized phase IV CF-GAIN trial showed.

The mean composite score on the Conners Continuous Performance test, second edition, assessing child attention, processing speed, and response inhibition skills, was 51 for kids who received repeated bronchoalveolar-lavage (BAL)-directed therapy with general anesthesia compared with 53 for those who received standard care with no planned lavages up to age 5 (P=0.32), reported Claire Elizabeth Wainwright, MD, of the University of Queensland in South Brisbane, Australia, and co-authors.

Secondary endpoints including intellectual function, other neurobehavioral measures, and brain imaging were also similar between the two groups, they noted in the .

"No clearly meaningful differences were observed between the group randomly assigned to receive a greater number of anesthetics and the group assigned to receive fewer general anesthetics," Wainwright and team wrote. "Additionally, there was no sign of a dose effect on neurocognitive or behavioral outcomes."

"Our study did observe small differences between the groups for grey matter and also for the body of the corpus callosum in the MRI scans," they added. "While the corpus callosum differences could be indicative of changes in white matter integrity in those exposed to general anesthesia, the differences were small and in the context of multiple comparisons these differences are likely due to chance."

While several observational studies have looked at the relationship between early general anesthesia exposure and later outcomes, they were limited by confounding of general anesthesia exposure with other factors affecting brain development and function. A showed that while exposure to general anesthetics could have the potential for neurotoxicity, there was little evidence to support this, since most studies were done in retrospective cohorts.

To study this association, Wainwright's group previously conducted the randomized , which showed that BAL-directed therapy did not result in a lower prevalence of Pseudomonas aeruginosa infection or lower total cystic fibrosis CT score when compared with standard therapy at age 5 years.

In an , Daniil P. Aksenov, MD, PhD, of NorthShore University HealthSystem in Evanston, Illinois, noted that duration of anesthesia exposure, as well as age at exposure, are both important factors.

"Although both groups were exposed to anesthesia, there were two main differences: the cumulative duration of anesthesia was longer in the BAL-directed therapy group compared with the standard-care group, and all patients in the BAL-directed therapy group were exposed to anesthesia during the first 2 years of life, whereas the majority of patients in the standard-care group were exposed to anesthesia between 2 and 6 years old," he wrote. "This raises the question of which age might be most vulnerable to the long-term adverse effects of anesthesia."

"Some studies attribute this vulnerability to ages up to 3 or even 6 years, but it is not clear which specific age group is most affected because preclinical models do not translate directly to human development due to substantial differences," he added. "It can be further hypothesized that the critical period is more prominent for up to 2 years, and the analysis can be adjusted by making the groups more distinct by removing patients who were exposed to anesthesia before the age of 2 years from the standard-care group."

For the open-label , Wainwright and colleagues included children who completed the ACFBAL trial (mean age 3.5-3.7 months at enrollment) and underwent standardized neurobehavioral and health-related quality-of-life assessment and brain MRI scans from October 2013 through June 2017 at a mean age of 12.8 years at three hospitals in Australia and one hospital in New Zealand.

Of the 97 children who consented to the study, 52 were randomly assigned to BAL-directed therapy under general anesthesia (56% boys) and 45 to standard care with no requirement for BAL-directed therapy (51% girls). Most patients were white.

The primary outcome was a composite score of performance on a standardized, computer-based assessment of child attention, processing speed, and response inhibition skills using the Conners Continuous Performance test, second edition. Secondary outcomes included intellectual function, other neurobehavioral measures, and brain imaging as an exploratory outcome.

At 2 years, the BAL-directed therapy group and the standard-care group had a median of two and zero exposures to general anesthesia, respectively. At completion of the ACFBAL trial, these groups had a median six exposures and two exposures, respectively, and at completion of CF-GAIN, they had a median of 10 and four exposures. For those with complete cumulative exposure time data to the end of the ACFBAL trial, the median cumulative exposure time for the BAL-directed therapy group (n=29) was 180 minutes, and 48 minutes for the standard-care group (n=32).

Wainwright and colleagues highlighted several limitations to their study. The trial only included children with cystic fibrosis, making the findings non-representative of the general population. Other limitations included the loss to follow-up of 42% of the original ACFBAL study cohort, the smaller sample size, and the short anesthesia duration in the BAL-directed therapy group.

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