Project Details

E.W. "Al" Thrasher

Status: Funded - Open

Neurocognitive outcomes 5 years after infant anesthesia: The GAS Trial

Mary Ellen McCann, MD, MPH


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 neurodevelopmentalimpairments 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: In this international assessor-masked equivalence RCT, infants less than 60 weeks’ postmenstrual age and born at greater than 26 weeks gestation undergoing inguinal herniorraphies without prior exposure to general anesthesia or risk factors for neurologic injury were recruited. They were randomly assigned to receive either an awake-regional or sevoflurane-based general anaesthetic. The primary outcome measure was the Wechsler Preschool and Primary Scale of Intelligence-Third Edition (WPPSI-III) Full Scale Intelligence Quotient (FSIQ) at 5 years of age. The primary analysis was as-per-protocol adjusted for gestational age at birth and country using multiple imputation to deal with missing data. An intention-to-treat analysis was also performed. A difference in means of five points was predefined as the clinical equivalence margin. Secondary outcomes included the Bayley 3 examination at 2 years of age and other neurocognitive and behavioral tests at age 2 and 5 years.

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 awakeregional anesthesia and 359 to general anesthesia. Outcome data for the 2 year evaluations 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. There were 74 protocol violations in the awake-regional group and 2 in the

general anaesthesia group. Primary outcome data for the as-per-protocol analysis were obtained from 205 children in the awake-regional group and 242 in the general anaesthesia group. The FSIQ score (mean [standard deviation (SD)]) was 99.08 (18.35) in the awake-regional group and 98.97 (19.66) in the general anaesthesia group, with a difference in means (awake-regional minus general anaesthesia) of 0.23, 95% Confidence Intervals -2.59 to 3.06) showing strong evidence of equivalence. The results with the intention-to-treat analysis were similar to the as-per-protocol analysis.

IMPACT: We found strong evidence that just under an hour of general anesthesia in early infancy does not alter neurodevelopmental outcome compared to awake-regional anesthesia in a predominantly male study population. This should allay the concerns of parents and care givers about the safety of general anesthesia for short to medium length procedures.


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.

Pinyavat T, Warner DO, Flick RP, McCann ME, Andropoulos DB, Hu D, Sall JW, Spann MN, Ing C.Summary of the Update Session on Clinical Neurotoxicity Studies. J Neurosurg Anesthesiol. 2016 Oct;28(4):356-360.

McCann, Mary Ellen, Jurgen C. De Graaff, Liam Dorris, Nicola Disma, Davinia Withington, Graham Bell, Anneke Grobler et al. "Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial." The Lancet 393, no. 10172 (2019): 664-677.

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.

Polaner, David M., Jeannie Zuk, Mary Ellen McCann, and Andrew Davidson. "Warnings, uncertainty, and clinical practice." The Lancet 389, no. 10085 (2017): 2174-2176.

Mccann, Mary E. "Perioperative factors influencing neurocognitive outcomes in infants." Minerva pediatrica 69, no. 4 (2017): 314-325.

Disma, Nicola, James D. O'Leary, Andreas W. Loepke, Ansgar M. Brambrink, Karin Becke, Nicola G. Clausen, Jurgen C. De Graaff et al. "Anesthesia and the developing brain: A way forward for laboratory and clinical research." Pediatric Anesthesia 28, no. 9 (2018): 758-763.

Disma, Nicola, Davinia Withington, Mary Ellen McCann, Rodney Wayne Hunt, Sarah Jane Arnup, Francesca Izzo, Jurgen C. de Graaff et al. "Surgical practice and outcome in 711 neonates and infants undergoing hernia repair in a large multicenter RCT: Secondary results from the GAS Study." Journal of pediatric surgery 53, no. 9 (2018): 1643-1650.

Gentry, Katherine R., Sarah J. Arnup, Nicola Disma, Liam Dorris, Jurgen C. de Graaff, Agnes Hunyady, Neil S. Morton et al. "Enrollment challenges in multicenter, international studies: The example of the GAS trial." Pediatric Anesthesia 29, no. 1 (2019): 51-58.