Society for Pediatric Anesthesia
We make anesthesia for children safer

Summary
Background
Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial.

Methods
In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks’ gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600.

Findings
Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awakeregional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-perprotocol analysis, the cognitive composite score (mean [SD]) was 98·6 (14·2) in the awakeregional group and 98·2 (14·7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0·169, 95% CI −2·30 to 2·64). The median duration of anaesthesia in the general anaesthesia group was 54 min.

Interpretation
For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia.

On Dec. 14, 2016 the U.S. Food and Drug Administration (FDA) issued a safety announcement regarding the potential effect of anesthetics on children younger than 3 years of age. Recent studies suggest that a single, relatively short exposure to general anesthetic and sedation drugs in infants or toddlers is unlikely to have negative effects on behavior or learning. However, further research is needed to fully characterize how early life anesthetic exposure affects children’s brain development. To better inform the public about this potential risk, we have taken points from the FDA’s communication and are sharing those with families to help them make educated decisions about the care of their young child.

Facts About General Anesthetic and Sedation Drugs

• General anesthetic and sedation drugs are used to put infants and children into a deep sleep so they do not feel pain during surgery or procedures.
• These drugs are usually injected into a vein or inhaled through a mask or breathing tube.
• General anesthetic drugs are used in millions of children every year to ensure their health, safety and comfort during surgery and other procedures.

Additional Information for Parents and Caregivers

• Anesthetic and sedation drugs are necessary for infants and children who require surgery or other painful or stressful procedures. Additionally, untreated pain can be harmful to children and their developing nervous systems.
• Research suggests that repeated or prolonged use of general anesthetic or sedative drugs may be associated with negative effects on the developing brain.
• These effects are subtle and may include learning, memory, or behavior problems.
• The FDA has issued a warning that this may affect children younger than 3 years who are undergoing anesthesia for more than three hours, or are exposed to repeated anesthetics.
• Recent studies in children suggest that a single, short duration exposure to general anesthetic and sedation drugs under age 3 years is unlikely to have negative effects on behavior or learning.
• No specific anesthetic or sedative medications have been shown to be safer than any other.
• Parents and caregivers should ask for information about the planned surgery or procedure, including duration of anesthesia and need for any repeated procedures.
• Parents should discuss with their anesthesiologist and surgeon the potential adverse effects of anesthesia and brain development and appropriate timing of procedures that could be delayed without jeopardizing their child’s health.
• Examples of life-threatening conditions in newborns and other children younger than 3 years that require surgery or other procedures that should not be delayed include, but are not limited to:
  • Congenital heart defects
  • Esophageal atresia, a disorder in which the esophagus does not develop properly
  • Intestinal blockage or twisting of the intestines
  • Gastroschisis and omphalocele, which are birth defects of the abdominal wall
  • Diaphragmatic hernia, which is a birth defect in which there is an abnormal opening in the diaphragm
  • Congenital lung lesions
  • Pyloric stenosis, which is a narrowing of the opening from the stomach into the small intestine
  • Craniofacial reconstruction
  • Complex urological reconstruction
• Examples of other common procedures for non-life-threatening conditions in children younger than 3 years that are necessary and should not be delayed are cleft lip or palate repair and surgery to repair undescended testicles in boys.
• If you have further questions about your child’s care, talk to your anesthesiologist and surgeon.
• Other useful resources:
  • SmartTots website: www.smarttots.org
  • Society for Pediatric Anesthesia website: pedsanesthesia.org
  • U.S. FDA Website: www.fda.gov

On Wednesday, December 14, the United States Food and Drug Administration (FDA) released a Drug Safety Communication warning that; “repeated or lengthy use of general anesthetic or sedation drugs during surgeries or procedures in children younger than three years of age or in pregnant women during the final trimester may affect development of children’s brains”. The FDA defined lengthy as greater than three hours of exposure.

While there is abundant animal data concerning suspected toxicities in prolonged and multiple anesthetics, the accumulated human data suggest that one brief anesthetic is not associated with cognitive or behavioral abnormalities in children. Most but not all studies in children do however suggest an association between repeated and or prolonged exposure and subsequent difficulties with learning or behavior. It is not yet known whether the anesthetic drug or some other factor is responsible for these findings. Rigorous research to further characterize any possible associations is ongoing.

The data reviewed by the FDA in making the decision to issue this labelling change have accumulated over more than a decade and has been discussed at three separate FDA advisory committee meetings since 2007. This warning appears to have been issued to raise awareness among practitioners and the public to ensure the information needed to make informed judgments about the risks and benefits of anesthesia and sedation in young children and pregnant women is widely available.

The potential risk of negative cognitive or behavioral effects of anesthetic agents remains uncertain and must be placed in the context of the known risks and benefits of both the anesthetic and the related surgical or diagnostic procedure for which the anesthetic is required. Clinicians and parents are cautioned against the possible risk of delaying needed surgical or diagnostic procedures. Until additional information is available from ongoing studies, parents and providers should carefully weigh the risk and benefit of each contemplated procedure before proceeding.

Click to read the complete FDA statement

Additional information may also be found at the following web site: smarttots.org. SmartTots is a public private partnership between the FDA and the International Anesthesia Research Society. The above statement represents a consensus of each of the following organizations all of which share a commitment to health and safety of children and pregnant women.