Project Details

E.W. "Al" Thrasher

Status: Funded - Open

Neurocognitive outcomes 5 years after infant anesthesia: The GAS Trial

Mary Ellen McCann, MD, MPH

Summary

BACKGROUND: Animal models, including primates, have shown that anesthetic and sedative agents cause increased rates of neuronal necrosis and apoptosis in the developing brain, as well as later learning deficits and human cohort studies have shown that young children exposed to general anesthetics have an increased incidence of later learning difficulties. These observational studies are flawed because they did not adequately address confounding factors that could lead to later neurodevelopmental impairments such as premorbid conditions requiring surgery (congenital anomalies, birth trauma, infection etc.) or the surgical experience itself.

GAP: To reduce confounding factors, a randomized prospective controlled trial has been conducted on a group of study subjects with no significant premorbid conditions who underwent uncomplicated surgery (inguinal herniorrhaphy).

HYPOTHESIS: At 5 years of age, the Full-scale IQ score on the Wechsler Preschool and Primary Scale of Intelligence-Third Edition (WPPSI-III) will be equivalent in children who received general anesthesia or regional awake anesthesia (i.e., the 2-sided 95% confidence interval for the adjusted treatment group difference in means lies within -5 and +5 points). We also hypothesize that the scores of children in the treatment groups will be equivalent on assessments of other specific neurocognitive domains.

METHODS: The GAS trial is an international prospective randomized equivalence trial comparing the neurocognitive effects of general anesthesia to regional anesthesia in infants undergoing inguinal herniorrhapy. Seven hundred and twenty two infants were enrolled and will undergo neurocognitive testing at age 2 and age 5.

RESULTS: Two year interim findings were published in the LANCET 2016. Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anesthesia and 359 to general anesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anesthesia group. There was equivalence in mean between groups (awake-regional minus general anesthesia 0.169, 95% CI -2.30 to 2.64). The median duration of anesthesia in the general anesthesia group was 54 min.

IMPACT: A significant treatment group difference at age 5 will mean that we need to develop anesthetic agents that are safer, recommend delaying elective surgery or consider foregoing sedation for pediatric procedures. If there is no difference, current concerns of parents and practitioners about anesthetic safety will be allayed.

Publications:

Frawley, Geoff, Graham Bell, Nicola Disma, Davinia E. Withington, Jurgen C. De Graaff, Neil S. Morton, Mary Ellen McCann et al. "Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia RepairData from the General Anesthesia Compared to Spinal Anesthesia Study—Comparing Apnea and Neurodevelopmental Outcomes." Anesthesiology: The Journal of the American Society of Anesthesiologists 123, no. 1 (2015): 55-65.

McCann, M. E., D. E. Withington, S. J. Arnup, A. J. Davidson, N. Disma, G. Frawley, N. S. Morton et al. "Differences in Blood Pressure in Infants After General Anesthesia Compared to Awake Regional Anesthesia (GAS Study—A Prospective Randomized Trial)." Anesthesia & Analgesia 125, no. 3 (2017): 837-845.

McCann, Mary Ellen, and Jurgen de Graaff. "Current thinking regarding potential neurotoxicity of general anesthesia in infants." Current opinion in urology 27, no. 1 (2017): 27-33.

Davidson, Andrew J., Neil S. Morton, Sarah J. Arnup, Jurgen C. De Graaff, Nicola Disma, Davinia E. Withington, Geoff Frawley et al. "Apnea after Awake Regional and General Anesthesia in InfantsThe General Anesthesia Compared to Spinal Anesthesia Study—Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial." Anesthesiology: The Journal of the American Society of Anesthesiologists 123, no. 1 (2015): 38-54.

Davidson, Andrew J., Nicola Disma, Jurgen C. de Graaff, Davinia E. Withington, Liam Dorris, Graham Bell, Robyn Stargatt et al. "Neurodevelopmental outcome at two years of age after general and awake-regional anaesthesia in infancy: a randomised controlled trial." Lancet (London, England) 387, no. 10015 (2016): 239.

Davidson, Andrew J., Karin Becke, Jurgen De Graaff, Gaia Giribaldi, Walid Habre, Tom Hansen, Rodney W. Hunt et al. "Anesthesia and the developing brain: a way forward for clinical research." Pediatric Anesthesia 25, no. 5 (2015): 447-452.

Colon, Elisabeth, Edward A. Bittner, Barry Kussman, Mary Ellen McCann, Sulpicio Soriano, and David Borsook. "Anesthesia, brain changes, and behavior: Insights from neural systems biology." Progress in neurobiology 153 (2017): 121-160.